CN115151540A

CN115151540A - Polyheterocyclic compounds as METTL3 inhibitors

Info

Publication number: CN115151540A
Application number: CN202080095149.6A
Authority: CN
Inventors: 韦斯利·彼得·布莱卡比; 大卫·詹姆斯·哈迪克; 伊丽莎白·简·托马斯; 弗雷德里克·阿瑟·布鲁克菲尔德; 约恩·谢泼德; 克里斯蒂安·布伯特; 马克·彼得·里吉尔
Original assignee: Storm Therapy Ltd
Current assignee: Storm Therapy Ltd
Priority date: 2019-12-02
Filing date: 2020-12-01
Publication date: 2022-10-04
Also published as: BR112022010561A2; US20230116403A1; KR20220113431A; EP4069694A1; CA3162166A1; JP2023506147A; US20230002378A1; IL293340A; JP7765088B2; AU2020394867A1; WO2021111124A1; US11725010B2; US20250122195A1; US12195458B2; MX2022006700A

Abstract

The present invention relates to compounds of formula (I) that act as inhibitors of METTL3 (N6-adenosine-methyltransferase 70kDa subunit) enzymatic activity: X-Y-Z (I), wherein X, Y and Z are each as defined herein. The invention also relates to processes for preparing these compounds, pharmaceutical compositions containing them, and their use in the treatment of proliferative disorders (e.g., cancer) and autoimmune diseases, as well as other diseases or disorders in which METTL3 activity is involved.

Description

Polyheterocyclic compounds as METTL3 inhibitors

Technical Field

The present invention relates to certain compounds that act as inhibitors of METTL3 (N6-adenosine-methyltransferase 70kDa subunit) activity. The invention also relates to methods for preparing these compounds, pharmaceutical compositions comprising them, and their use in treating proliferative disorders (e.g., cancer), autoimmune, neurological, infectious, and inflammatory diseases, as well as other diseases or disorders in which METTL3 activity is implicated.

Background

N6-methyladenosine (m 6A) is the most common and most abundant covalent modification of messenger RNA, regulated by the markers "writer (writer)", "eraser (eraser)" and "reader (reader)" (Meyer & Jaffrey 2014, niu Y et al,2013, yue et al 2015). About 0.1% to 0.5% of all mRNA adenosines are modified with m6A (Li Y et al 2015). In vitro data show that m6A affects essential aspects of mRNA biology, mainly mRNA expression, splicing, stability, localization and translation (Meyer et al,2015, sledz &jinek 2016). M6A modification is tissue specific and there is a significant change in its occurrence profile in non-diseased tissues (e.g. brain, heart, kidney) as well as diseased tissues and cells (lung, kidney, breast and leukemic cancer cells) (Meyer et al 2012).

The m6A modification and its erasers and writers, such as FTO, ALKBH5, methyltransferase-like 3 (mettl3) and METTL14, are associated with major diseases such as solid organ cancer, leukemia, type 2 diabetes, neuropsychiatric behavioural disorders and depression (Chandola et al 2015, koranda et al 2018.

The RNA methyltransferase METTL3 is the major, but not the only, enzyme that catalyzes the m6A modification of RNA. It exists as a heterotrimeric complex with METTL14 (Liu et al 2014, wang et al 2016) and Wilm's Tumour Associated Protein (WTAP) (Ping et al 2014). Catalytic activity is present in METTL3, which transfers a methyl group from the cofactor S-adenosylmethionine to the substrate RNA, and METTL14 promotes substrate RNA binding. WTAP localizes the complex to a specific nuclear region and also localizes the RNA substrate to the complex (Wang X et al 2016).

METTL3 is reported to play a role in many aspects of carcinogenesis (Fry et al 2018). Genetic knockdown of METTL3 in lung cancer cell lines (a 549, H1299, and H1792) and HeLa cells resulted in decreased growth, survival, and invasion of human lung cancer cells (Lin S et al 2016). METTL3 is significantly upregulated in human bladder cancer (Cheng et al 2019). Knockdown of METTL3 significantly reduces proliferation, invasion and survival of bladder cancer cells in vitro and tumorigenicity in vivo. AF4/FMR2 family member 4 (AFF 4), two key regulators of the NF- κ B pathway (IKBKB and RELA), and MYC were also identified as direct targets for METTL 3-mediated m6A modification. In renal cancer cell lines (CAK-1, CAK-2, and ACHN), genetic knockdown reduces cell proliferation through the phosphatidylinositol 3-kinase (PI 3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway (Li X et al 2017).

Barbieri et al (2017) recently defined a group of RNA modifying enzymes essential for AML leukemia and identified a key leukemic pathway for METTL3 RNA methyltransferase. In this pathway, METTL3 is stably recruited by the CCAAT-box binding transcription factor CEBPZ to the promoter of a particular set of active genes, resulting in m6A methylation of the respective mRNA and increased translation. One important target is the oncogene SP1 in several cancers, which regulates c-MYC expression. Consistent with these findings, METTL3 has been reported to co-transcriptionally methylate its target.

The pathway described by Barbieri et al is critical for AML leukemia because its three components are required for AML cell growth: (i) m6A RNA methyltransferase METTL3; (ii) the transcription factor CEBPZ which targets the enzyme to the promoter; and (iii) SP1, whose translation is dependent on m6A modification by METTL 3. In summary, barbieri et al observations define METTL3 enzyme activity as a new candidate target for the treatment of AML.

In a separate independent study, METTL3 has been reported to play an important role in controlling myeloid differentiation of normal hematopoietic and leukemic cells in mammals (Vu et al 2017). Forced expression of wild-type METTL3, but not mutant METTL3 (deficient in catalytic activity) significantly promoted cell proliferation and inhibited cell differentiation of human cord blood-derived CD34+ hematopoietic stem/progenitor cells (HSPCs). Genetic knockdown of METTL3 has the opposite effect. METTL3 is highly expressed in AML compared to normal HSPC or other types of cancer. Knockdown of METTL3 in human AML cell lines significantly induced cell differentiation and apoptosis and inhibited leukemia progression in mice xenografted with MOLM-13AML cells. The biological function of METTL3 may be attributed to promoting translation of its mRNA targets such as MYC, BCL-2, and PTEN in an m 6A-dependent manner.

More recently, METTL3 mediated m6A modification has been demonstrated to play an important role in T cell homeostasis and signal-dependent induction of mRNA degradation in CD4 positive T cell lineage (Li et al 2017). Deletion of METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a mouse adoptive transfer model of lymphopenia, naive Mettl3 deficient T cells failed to undergo steady state expansion and remained naive for up to 12 weeks, thereby preventing colitis. Consistent with these observations, mRNA encoding the SOCS family genes for STAT signaling inhibitory proteins SOCS1, SOCS3 and CISH was labeled with m6A, which showed slower mRNA decay and showed increased mRNA and protein expression levels in Mettl 3-deficient naive T cells. This increased activity of the SOCS family thus inhibits IL-7 mediated STAT5 activation and T cell homeostatic proliferation and differentiation. METTL3 mediated m6A methylation therefore has an important role for inducible degradation of Socs mRNA in response to IL-7 signaling in order to reprogram naive T cells for proliferation and differentiation, suggesting a role in autoimmunity.

Recent studies have revealed that depletion of METTL3 leads to alterations in the propagation of different viruses (Winkler et al). Deletion of the m6A "writer" METTL3 resulted in increased induction of the interferon-stimulated gene following viral infection or stimulation of cells with inactivated virus. Thus, the propagation of different viruses is inhibited in an interferon signaling dependent manner. Notably, mRNA of IFNB was modified by m6A and stabilized after METTL3 inhibition. m6A acts as a negative regulator of interferon response by indicating a rapid switch in interferon mRNA and thus promoting viral propagation.

METTL 3-dependent m6A on HBV and HCV viral genomes regulates recognition of the viral genome by RIG-IRNA sensors. Depletion of METTL3 enhances viral dsRNA recognition and induces an antiviral immune response (Kim et al).

Thus, METTL3 inhibitors may provide novel therapeutic approaches to treat a range of infectious and inflammatory diseases. In particular, it provides a potential treatment for viral diseases (e.g., DNA and RNA viruses).

Furthermore, METTL 3-dependent m6A on endogenous mRNA modulates recognition by MAVS-dependent RNA sensors. Depletion of METTL3 enhances endogenous dsRNA recognition and induces an autoimmune response (Gao et al). This means that anti-tumor immune responses can be enhanced by METTL3 inhibition.

Thus, METTL3 inhibitors may also provide novel therapeutic approaches to enhance anti-tumor immune responses.

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It is an object of the present invention to provide inhibitors of METTL3 activity.

Disclosure of Invention

In one aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a pharmaceutical composition as defined herein, comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

In another aspect, the invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in therapy.

In another aspect, the invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in the treatment of a proliferative disorder.

In another aspect, the invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a specific embodiment, the cancer is a human cancer.

In another aspect, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in inhibiting METTL3 activity.

In another aspect, the invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in promoting an immune response (e.g., an antiviral or antitumor immune response).

In another aspect, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in enhancing an innate immune response in a subject.

In another aspect, the invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in enhancing or potentiating an anti-tumour immune response during an immunooncological treatment.

In another aspect, the invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in the treatment of an autoimmune disease.

In another aspect, the invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in the treatment of a neurological disease.

In another aspect, the invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in the treatment of an infectious disease.

In another aspect, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in the treatment of a viral infection. Suitably, the viral infection is an RNA viral infection. Suitably, the viral infection is Human Papilloma Virus (HPV) or hepatitis.

In another aspect, the invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein for use in the treatment of an inflammatory disease.

In another aspect, the invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. In a specific embodiment, the medicament is for treating cancer in a human.

In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting METTL3 activity.

In another aspect, the invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for promoting an immune response (e.g. an anti-viral or anti-tumour immune response).

In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for increasing an innate immune response in a subject.

In another aspect, the invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for increasing or enhancing an anti-tumour immune response during immunooncological treatment.

In another aspect, the invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an autoimmune disease.

In another aspect, the invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological disease.

In another aspect, the invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an infectious disease.

In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a viral infection. Suitably, the viral infection is an RNA viral infection. Suitably, the viral infection is Human Papilloma Virus (HPV) or hepatitis.

In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an inflammatory disease.

In another aspect, the invention provides a method of inhibiting METTL3 activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

In another aspect, the invention provides a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

In another aspect, the invention provides a method of inhibiting metastasis in vitro or in vivo, comprising contacting a cell with an effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of promoting an immune response (e.g. an anti-viral or anti-tumour immune response) in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of increasing an innate immune response in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of increasing or enhancing an anti-tumour immune response during an immunooncological treatment, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treating a proliferative disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treating an autoimmune disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treating a neurological disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treating an infectious disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a method of treating a viral infection, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein. Suitably, the viral infection is an RNA viral infection. Suitably, the viral infection is Human Papilloma Virus (HPV) or hepatitis.

In another aspect, the present invention provides a method of treating an inflammatory disease, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

In another aspect, the invention provides a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

The invention also provides a method of synthesising a compound or pharmaceutically acceptable salt as defined herein.

In another aspect, the invention provides a compound or pharmaceutically acceptable salt as defined herein obtainable or obtained by or directly by a synthetic method as defined herein.

In another aspect, the present invention provides a novel intermediate as defined herein, suitable for use in any one of the synthetic methods as described herein.

Preferred, suitable and optional features of any particular aspect of the invention are also preferred, suitable and optional features of any other aspect.

Detailed Description

Definition of

Unless otherwise indicated, the following terms used in the specification and claims have the meanings set forth below.

It will be understood that reference to "treating" includes both prevention and alleviation of established symptoms of the disorder. Thus, "treatment" of a condition, disorder or condition includes: (ii) preventing or delaying the occurrence of clinical symptoms of the state, disorder or condition occurring in a human who may be suffering from or susceptible to the state, disorder or condition, but does not yet experience or exhibit clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., preventing (arrest), reducing or delaying the occurrence of disease or its recurrence (in the case of maintenance therapy) or at least one of its clinical or subclinical symptoms, or (3) relieving or alleviating the disease, i.e., causing regression of the state, disorder or condition or regression of at least one of its clinical or subclinical symptoms.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a mammal to treat a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

In this specification, the term "alkyl" includes both straight-chain and branched alkyl groups. References to a single alkyl group such as "propyl" are specific to the straight chain version only, while references to a single branched alkyl group such as "isopropyl" are specific to the branched chain version only. For example, "C _1-6 Alkyl "includes C _1-4 Alkyl radical, C _1-3 Alkyl, propyl, isopropyl and tert-butyl. Similar convention applies to other groups, e.g. "phenyl (C) _1-6 Alkyl) "includes phenyl (C) _1-4 Alkyl), benzyl, 1-phenylethyl and 2-phenylethyl.

The terms "(m-nC)" or "Cm-n" or "(m-nC) group" or "Cm-n", used alone or as a prefix, refer to any group having m to n carbon atoms.

The term "alkenyl" as used herein refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls," the latter of which refers to an alkenyl moiety having a substituent that replaces a hydrogen on one or more carbons of the alkenyl. Such substituents may be present on one or more carbons that may or may not be included in one or more double bonds. Further, as discussed below, such substituents include all substituents intended for alkyl groups unless stability is limited. For example, it is contemplated that alkenyl groups may be substituted with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups.

The term "alkynyl" as used herein refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls," the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl. Such substituents may be present on one or more carbons that may or may not be included in one or more triple bonds. Further, as discussed above, such substituents include all substituents contemplated for alkyl groups unless stability is limited. For example, it is contemplated that an alkynyl group is substituted with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups.

An "alkylene" group is an alkyl group that is located between and serves to link two other chemical groups. Thus, "C _1-3 By alkylene "is meant a straight chain saturated divalent hydrocarbon group of 1 to 3 carbon atoms or a branched saturated divalent hydrocarbon group of three atoms, such as methylene, ethylene, propylene, and the like.

The term "C _m-n Cycloalkyl "means a hydrocarbon ring containing m to n carbon atoms, e.g." C _3-6 Cycloalkyl "means a hydrocarbon ring containing from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The term "C _m-n Cycloalkyl "also encompasses non-aromatic saturated or partially saturated monocyclic, fused, bridged or spiro bicyclic carbocyclic ring systems. The term "C _m-n Cycloalkyl "includes both monovalent and divalent species. Monocyclic ring of _m-n A cycloalkyl "ring contains about 3 to 12 (suitably 3 to 8, most suitably 5 to 6) ring carbon atoms. Bicyclic ring "C _m-n Cycloalkyl "contains from 7 to 17 ring carbon atoms, suitably from 7 to 12 ring carbon atoms. Bicyclic ring of C _m-n Cycloalkyl "rings may be fused, spiro or bridged ring systems.

The term "cycloalkoxy" means a cycloalkyl-O-group, wherein cycloalkyl is as previously defined, e.g. C _3-4 Cycloalkoxy (or-O-C) _3-4 Cycloalkyl) means a hydrocarbon ring containing 3 to 4 carbon atoms, linked to an O atom, such as:

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

The terms "heterocyclyl", "heterocyclic" or "heterocycle" mean a non-aromatic saturated or partially saturated monocyclic, fused, bridged or spiro bicyclic heterocyclic ring system. The term heterocyclyl includes both monovalent and divalent species. Monocyclic heterocycles comprise about 3 to 12 (suitably 3 to 7, most suitably 5 to 6) ring atoms, of which 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulphur are in the ring. Bicyclic heterocycles comprise 7 to 17 membered atoms in the ring, suitably 7 to 12 membered atoms. Bicyclic heterocycles comprise about 7 to about 17 ring atoms, suitably 7 to 12 ring atoms. The bicyclic heterocycle may be a fused, spiro or bridged ring system. Some examples of heterocyclic groups include cyclic ethers such as oxirane, oxetane, tetrahydrofuranyl, bis

Alkyl and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Dian (Chinese character)Sulfur-containing heterocycles of the type include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran and hexahydrothiopinane. Other heterocycles include dihydro-oxathiadienyl, tetrahydro-oxathianyl

Azolyl, tetrahydro-

Oxadiazolyl and tetrahydrodiazolyl

Azolyl, tetrahydro-

Thiazolyl, hexahydrotriazinyl, tetrahydro-

Oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, di

Oxazolinyl (dioxolinyl), octahydrobenzofuranyl, octahydrobenzimidazolyl and octahydrobenzothiazolyl. For sulfur-containing heterocycles, also included are those containing SO or SO ₂ Sulfur oxide heterocycles of group. Some examples include sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values for heterocyclyl radicals having 1 or 2 oxo (= O) or thio (= S) substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Specific heterocyclyl groups are saturated monocyclic 3-to 7-membered heterocyclyl groups containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl 1,1-dioxide, piperidinyl, homomorpholinyl, thiomorpholinyl 1,1-dioxide Piperidinyl (homoperidinyl), piperazinyl or homopiperazinyl (homopiperazinyl). As the skilled person will appreciate, any heterocyclic ring may be attached to another group via any suitable atom (e.g. via a carbon or nitrogen atom). However, reference herein to piperidinyl or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring attached through a ring nitrogen.

"carbon-linked heterocyclyl" means a heterocyclyl group, as defined above, that is linked through a carbon atom rather than a heteroatom (e.g., nitrogen).

By "spirocyclic ring system" is meant a compound having at least two rings that have only one atom in common and are not connected by a bridge.

By "fused ring system" is meant a compound in which two rings share two adjacent atoms. In other words, the rings share a covalent bond.

"bridged ring system" means a ring system in which two rings share more than two atoms, see, for example, advanced Organic Chemistry by Jerry March, 4 th edition, wiley Interscience, pages 131 to 133, 1992. Some examples of bridged heterocyclic ring systems include aza-bicyclo [2.2.1] heptane, 2-oxa-5-azabicyclo [2.2.1] heptane, aza-bicyclo [2.2.2] octane, aza-bicyclo [3.2.1] octane, and quinuclidine.

The term "heteroaryl" or "heteroaromatic" means an aromatic monocyclic, bicyclic or polycyclic ring incorporating one or more (e.g. 1 to 4, especially 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent and divalent species. Some examples of heteroaryl groups are monocyclic and bicyclic groups comprising five to twelve ring members, and more typically five to ten ring members. Heteroaryl groups may be, for example, 5-or 6-membered monocyclic or 9-or 10-membered bicyclic rings, such as bicyclic structures formed by fused five-and six-membered rings or two fused six-membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring comprises at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring may be basic (as in the case of imidazole or pyridine) or substantially non-basic (as in the case of indole or pyrrole nitrogens). Typically, the number of basic nitrogen atoms (including any amino substituents of the ring) present in the heteroaryl group will be less than five.

Some examples of heteroaryl groups include furyl, pyrrolyl, thienyl, and the like,

Azolyl radical, iso

Oxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,

Oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, and benzofuranyl

Oxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolyl, pyridopyrazinyl, thieno [2,3-b]Furyl, 2H-furo [3,2-b]-pyranyl, 5H-pyrido [2,3-d]-o-

Azinyl, 1H-pyrazolo [4,3-d]

Azolyl, 4H-imidazo [4,5-d]Thiazolyl, pyrazino [2,3-d]Pyridazinyl, imidazo [2,1-b]Thiazolyl, imidazo [1,2-b][1,2,4]A triazine group. "heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems wherein at least one ring is aromatic and one or more other rings are non-aromatic, saturated or partially saturated, provided that at least one ring comprises one or more rings selected from nitrogenHeteroatoms of oxygen or sulfur. Some examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo [1,4 ]II

Alkenyl, benzo [1,3]Dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido [2,3-b]Pyrazinyl and 3,4-dihydro-2H-pyrido [3,2-b][1,4]

An oxazine group.

Some examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl,

Azole group,

A diazolyl group,

Triazolyl, iso

Oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl.

Some examples of six membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

The bicyclic heteroaryl may be, for example, a group selected from:

a benzene ring fused with a 5-or 6-membered ring containing 1,2 or 3 ring heteroatoms;

a pyridine ring fused to a 5 or 6 membered ring containing 1,2 or 3 ring heteroatoms;

a pyrimidine ring fused to a 5 or 6 membered ring containing 1 or 2 ring heteroatoms;

a pyrrole ring fused to a 5 or 6 membered ring comprising 1,2 or 3 ring heteroatoms;

a pyrazole ring fused to a 5-or 6-membered ring comprising 1 or 2 ring heteroatoms;

a pyrazine ring fused to a 5 or 6 membered ring containing 1 or 2 ring heteroatoms;

An imidazole ring fused to a 5-or 6-membered ring comprising 1 or 2 ring heteroatoms;

condensed with 5-or 6-membered rings containing 1 or 2 ring hetero atoms

An azole ring;

hetero rings condensed with 5-or 6-membered rings containing 1 or 2 ring hetero atoms

An azole ring;

a thiazole ring fused with a 5-or 6-membered ring containing 1 or 2 ring heteroatoms;

an isothiazole ring fused with a 5-or 6-membered ring containing 1 or 2 ring heteroatoms;

a thiophene ring fused to a 5 or 6 membered ring containing 1, 2 or 3 ring heteroatoms;

a furan ring fused to a 5 or 6 membered ring comprising 1, 2 or 3 ring heteroatoms;

a cyclohexyl ring fused to a 5 or 6 membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; and

a cyclopentyl ring fused to a 5 or 6 membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms.

Some specific examples of bicyclic heteroaryls comprising a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl

Azolyl, benzisoyl

Azolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranPyranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adenine, guanine), indazolyl, benzodioxolyl, and pyrazolopyridinyl.

Some specific examples of bicyclic heteroaryls comprising two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodiazepine

Alkyl, quinolizinyl, benzo

Azinyl, benzodiazinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

The term "aryl" means a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Some examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In one embodiment, aryl is phenyl.

The term "optionally substituted" refers to substituted and unsubstituted groups, structures or molecules.

When the optional substituents are selected from "one or more" groups, it is understood that the definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

The phrase "compounds of the present invention" means those compounds generally and specifically disclosed herein.

Compounds of the invention

In one aspect, the invention relates to a compound of formula (I) shown below:

X-Y-Z

(I)

Wherein:

x is selected from:

wherein

Q ₁ Selected from NH, N-C _1-4 Alkyl, O or S;

Q _2a selected from N or CR _2a ；

Q _2b Selected from N or CR _2b ；

Q _2c Selected from N or CR _2c ；

Q _2d Selected from N or CR _2d ；

Q ₃ Selected from N or CR _1b ；

Q ₄ Selected from N or CR _1x ；

The precondition satisfied is Q ₁ 、Q _2a 、Q _2b 、Q _2c 、Q _2d 、Q ₃ And Q ₄ No more than 3 of which are nitrogen; r _1a Selected from:

(i)C _1-4 alkyl or C _1-4 Alkoxy, each of which is optionally substituted by halogen, cyano, hydroxy, C _3-6 Cycloalkyl radical, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, aryl or heteroaryl substitution; or

(ii) A group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is an integer selected from 0, 1, 2 or 3,

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a base compound,

(ii)C _1-6 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group; and wherein C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally further substituted with halogen, cyano or hydroxy;

(iii)C _3-4 cycloalkyl or 3-to 5-membered heterocyclyl, each of which is optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Is substituted in which R _1ca And R _1da Is H or C _1-2 An alkyl group; and

(iv) Or R _1c And R _1d Are linked together such that they form, together with the carbon atom to which they are attached, a 3 to 6 membered cycloalkyl or heterocyclic ring or a spiro ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group;

R _1e and R _1f Each independently selected from:

(i) Hydrogen (including deuterium);

(ii)C _1-6 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (1), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

(iii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 0, 1, 2, 3, 4, 5 or 6;

R _1g and R _1h Independently selected from:

a) Hydrogen;

b)C _1-6 alkyl, optionally substituted by one or more groups selected from cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (1), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano, or hydroxy;

c) aryl-C _1-6 Alkyl, heteroaryl C _1-6 Alkyl radical, C _3-6 Cycloalkyl or C _3-6 Cycloalkyl radical C _1-6 Alkyl, each of which is optionally selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; or

d) Or R _1g And R _1h Optionally linked together such that they form, together with the carbon atom to which they are attached, a 3 to 6 membered cycloalkyl or heterocyclic ring, optionally selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group;

and T ₁ Selected from hydrogen, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl), C _3-8 Cycloalkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (A), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

(iv) Or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (1), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro-fused which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0- ₂ R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group;

R _1b selected from hydrogen, cyano, halogen or C _1-3 An alkyl group;

R _1x selected from hydrogen, cyano, halogen or C _1-3 An alkyl group;

R _2a 、R _2b 、R _2c and R _2d Independently selected from hydrogen, cyano, halogen or a group of the formula:

-L _2a -L _2b -Q ₂

wherein

L _2a Is absent or optionally substituted by C _1-2 Alkyl or oxo substituted C _1-3 An alkylene group;

L _2b absent or selected from O, S, SO ₂ 、N(R _n )、C(O)、C(O)O、OC(O)、C(O)N(R _n )、N(R _n )C(O)、N(R _n )C(O)N(R _o )、S(O) ₂ N(R _n ) Or N (R) _n )SO ₂ Wherein R is _n And R _o Each independently selected from hydrogen or C _1-2 An alkyl group; and is provided with

Q ₂ Is hydrogen, cyano, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by a group selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, aminosulfonyl, C _1-4 Alkyl, NR _p R _q 、OR _p 、C(O)R _p 、C(O)OR _p 、OC(O)R _p 、C(O)N(R _p )R _q 、N(R _r )C(O)R _p 、S(O) _y R _p (wherein y is 0, 1 or 2), SO ₂ N(R _p )R _q 、N(R _r )SO ₂ R _p Or (CH) ₂ ) _z NR _p R _q (wherein z is 1, 2 or 3) wherein R is _p And R _q Each independently selected from hydrogen or C _1-4 An alkyl group; y is selected from:

wherein:

R _3a1 、R _3b1 、R _3c1 、R _3d1 、R _3e1 、R _3f1 、R _3g1 、R _3h1 、R _3i1 、R _3j1 、R _3k1 、R _3l1 、R _3m1 、R _3n1 、R _3o1 、R _3p1 、R _3q1 、R _3r1 and R _3s1 Independently selected from hydrogen (including deuterium), C _1-6 Alkyl radical, C _3-4 Cycloalkyl, hydroxy and halogen; and wherein C _1-6 Alkyl or C _3-4 Cycloalkyl is optionally substituted with one or more substituents selected from halogen, amino, cyano, and hydroxy;

R _3a2 、R _3b2 、R _3c2 、R _3d2 、R _3e2 、R _3f2 、R _3g2 、R _3h2 、R _3i2 、R _3j2 、R _3k2 、R _3l2 、R _3m2 、R _3n2 、R _3o2 、R _3p2 、R _3q2 、R _3r2 and R _3s2 Is hydrogen or halogen;

provided that R _3a1 、R _3b1 、R _3i1 、R _3l1 、R _3o1 、R _3r1 、R _3a2 、R _3b2 、R _3i2 、R _3l2 、R _3o2 And R _3s1 Cannot be halogen when n =1 or when n =2 and the carbon atom to which it is attached to an oxygen or nitrogen atom;

or R _3a1 And R _3a2 、R _3b1 And R _3b2 、R _3c1 And R _3c2 、R _3d1 And R _3d2 、R _3e1 And R _3e2 、R _3f1 And R _3f2 、R _3g1 And R _3g2 、R _3h1 And R _3h2 、R _3i1 And R _3i2 、R _3j1 And R _3j2 、R _3k1 And R _3k2 、R _3l1 And R _3l2 、R _3m1 And R _3m2 、R _3n1 And R _3n2 、R _3o1 And R _3o2 、R _3p1 And R _3p2 、R _3q1 And R _3q2 Or R _3r1 And R _3r2 Or R _3s1 And R _3s2 May be linked such that they form together with the carbon atoms to which they are attached a spiro-fused C _3-4 Cycloalkyl optionally substituted by one selected from halogen, methyl, amino, cyano and hydroxyOr more substituents;

n is 0, 1 or 2;

z is selected from one of the following structures:

i)

wherein:

B ₁ is A ₅ Wherein A is ₅ Selected from the group consisting of CR ₁₆ And N, wherein R ₁₆ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, 5-or 6-membered heteroaryl, C _1-4 Alkoxy radical, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _3-4 Cycloalkyl, 3-to 4-membered heterocyclyl and C _3-4 A cycloalkoxy group;

B ₂ is A ₆ Wherein A is ₆ Selected from N or CR ₁₇ Wherein R is ₁₇ 、R _H2 、R _H4 And R _H5 Selected from hydrogen, hydroxy, halogen, cyano, C _1-5 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Halogenoalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon-linked), wherein m is an integer from 1 to 6- (OCH ₂ CH ₂ ) _m -NR _q R _r 、-(OCH ₂ CH ₂ ) _m -OCH ₃ ，NR _q R _r ，-C(O)-NR _q R _r ，-C(O)OR _q ，

Wherein R is _q And R _r Each independently of the other is hydrogen, C _1-5 Alkyl radical, C _3-6 Cycloalkyl, 3-to 6-membered carbon-linked heterocyclyl, or R _q And R _r Are linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring;

wherein any C _1-5 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a substituent selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

B ₃ is N or CR _Z1 Wherein R is _Z1 Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl radicals of which C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally substituted with one or more of halo, methyl, or methoxy;

B ₄ Is selected from C or N;

B ₅ selected from the group consisting of CR _zi1b Or NR _B5N Wherein:

R _Zi1b selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 An alkoxy group; and is

R _B5N Selected from hydrogen or C _1-4 An alkyl group;

B ₇ is N, NR _Z2N Or CR _Z2 Wherein R is _Z2 Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 An alkoxy group; and R is _Z2N Selected from hydrogen or C _1-4 An alkyl group;

B ₈ selected from C or N;

provided that B is ₁ To B ₈ No more than four of which are N.

ii)

Y ₂ Is A ₇ Wherein A is ₇ Selected from the group consisting of CR ₁₈ And N; wherein R is ₁₈ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _3-4 Cycloalkyl, 3-to 4-membered heterocyclyl and C _3-4 A cycloalkoxy group;

Y ₃ is N or CR _z1a Wherein R is _Z1a Selected from hydrogen, hydroxy, C _1-4 Alkyl, cyano, halogen, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl radicals of which C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally substituted with one or more of halo, methyl, or methoxy;

Y ₄ is C or N;

Y ₅ is C-R _Y5 Or NR _Y5N Wherein:

R _Y5 selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 An alkoxy group;

R _Y5N selected from hydrogen or C _1-4 An alkyl group;

Y ₆ is C-R _Zi2e Or N, wherein R _Zi2e Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 An alkoxy group;

Y ₇ is O, S, CR _Z2a Or N, wherein R _Z2a Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 An alkoxy group;

Y ₈ is C or N;

Y ₉ is CR _Z3a Or N; wherein

R _Z3a Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 An alkoxy group;

provided that Y ₁ To Y ₈ No more than four of which are N.

(iii)

X ₁ Is N or C-R _Z9 Wherein R is _Z9 Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

X ₂ selected from N or CR ₄ Wherein:

R ₄ selected from the group consisting of hydrogen, halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy (e.g., hydrogen, halogen, cyano, and methyl);

X ₃ is N;

X ₄ is N or C;

X ₅ selected from N, CR ₅ And CRx _5a R _X5b Wherein:

R ₅ selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and methyl);

Rx _5a and R _X5b Independently selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and methyl);

or:

X ₆ is A ₁ And X ₇ Is A ₂ (ii) a Or

X ₆ Is A ₈ And X ₇ Is A ₉ Or A ₁₁ Wherein:

A ₁ selected from the group consisting of CR ₁₂ And N; wherein

R ₁₂ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy and C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and C) _1-4 Alkyl);

A ₂ selected from the group consisting of CR ₁₃ And N, wherein:

R ₁₃ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, methoxy, and methyl);

A ₈ selected from the group consisting of CR ₁₉ R ₂₀ And NR ₂₁ (ii) a Wherein:

R ₁₉ and R ₂₀ Independently selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and C) _1-4 Alkyl groups);

R ₂₁ is hydrogen or C _1-4 An alkyl group.

A ₉ Selected from the group consisting of CR ₂₂ R ₂₃ And NR ₂₄ ；

Wherein R is ₂₂ And R ₂₃ Independently selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and methyl);

R ₂₄ selected from hydrogen or C _1-4 An alkyl group;

A ₁₁ selected from the group consisting of CR ₂₈ R ₂₉ And NR ₃₀ ；

R ₂₈ And R ₂₉ Selected from hydrogen, halogen, methoxy and methyl;

R ₃₀ selected from hydrogen or C _1-4 An alkyl group.

X ₈ Selected from the group consisting of CR ₆ N or CR _X6a R _X6b ；

Wherein R is ₆ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy and C _1-4 A haloalkoxy group;

R _X6a and R _X6b Each independently selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy and C _1-4 A haloalkoxy group;

X ₉ is N or C;

provided that X ₂ To X ₉ No more than four of which are N.

(iv)

Z ₁₀ Is N or C-R _Z10 Wherein R is _Z10 Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

Z ₁₁ Is N or C-R _Z11 Wherein R is _Z11 Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

Z ₁₂ is N or C-R _Z12 Wherein R is _Z12 Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

Z ₁₃ is N or C-R _Z13 Wherein R is _Z13 Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

Z ₁₄ is N or C-R _Z14 Wherein R is _Z14 Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

Z ₁₅ is N or C-R _Z15 Wherein R is _Z15 Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

Z ₁₆ is N or C-R _Z16 Wherein R is _Z16 Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

provided that Z ₁₀ To Z ₁₆ No more than three of which are N;

(v)

Q ₇ is CR ₇ Or N;

Q ₈ is CR ₈ Or N;

Q ₉ is CR ₉ Or N;

Q ₁₀ is CR ₁₀ Or N;

Q ₁₁ is CR ₁₁ Or N;

Q _11a is NR _11N Or CR _11a R _11b ；

Wherein R is ₇ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R _11a And R _11b Each independently selected from hydrogen, NH ₂ Halogen, cyano, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-6 Alkyl, -CH ₂ OCH ₃ 、-CH ₂ SO ₂ CH ₃ 、-SO ₂ CH ₃ 、-NHC(O)CH ₃ and-C (O) NR _v1 R _v2 Wherein R is _v1 And R _v2 Independently selected from hydrogen and methyl, and; and R is _11N Selected from hydrogen, NH ₂ Halogen, cyano and C _1-6 An alkyl group;

or

R ₉ And R ₁₀ May be linked together such that they form, together with the atoms to which they are attached, a fused 5-or 6-membered saturated or unsaturated ring system, or R ₁₀ And R ₁₁ May be linked together such that they form, together with the atoms to which they are attached, a fused 5-or 6-membered saturated or unsaturated ring system, wherein the fused 5-or 6-membered saturated or unsaturated ring system may optionally be selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 HalogenatedAlkoxy, NR _1ia R _1ja or-S (O) _0- ₂ R _1ia R _1ja Wherein R is substituted with one or more substituents of (A), wherein R is _1ia And R _1ja Is H or C _1-2 An alkyl group;

provided that Q is ₇ To Q ₁₁ No more than three of which are N.

In another aspect, the invention relates to a compound of formula (I) shown below:

X-Y-Z

(I)

wherein:

x is selected from:

wherein

Q ₁ Selected from NH, N-C _1-4 Alkyl, O or S;

Q _2a selected from N or CR _2a ；

Q _2b Selected from N or CR _2b ；

Q _2c Selected from N or CR _2c ；

Q _2d Selected from N or CR _2d ；

Q ₃ Selected from N or CR _1b ；

Q ₄ Selected from N or CR _1x ；

(i)C _1-4 alkyl or C _1-4 Alkoxy, each of which is optionally substituted by halogen, cyano, hydroxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, aryl or heteroaryl substitution; or

(ii) A group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ;

wherein

p is an integer selected from 0, 1, 2 or 3,

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a salt thereof,

(iii)C _3-4 cycloalkyl or 3-to 5-membered heterocyclyl, each of which is optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Substituted in which R _1ca And R _1da Is H or C _1-2 An alkyl group;

(iv) Or R _1c And R _1d Are linked together such that they form, together with the carbon atom to which they are attached, a 3 to 6 membered cycloalkyl or heterocyclic ring or a spiro ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (1), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group;

R _1e and R _1f Each independently selected from:

(i) Hydrogen (including deuterium);

(ii)C _1-6 alkyl, optionally substituted by one or more substituents selected from cyano, oxo, hydroxy 、C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

(iii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 0, 1, 2, 3, 4, 5 or 6;

R _1g and R _1h Independently selected from:

a) Hydrogen;

b)C _1-6 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy; or alternatively

c) aryl-C _1-6 Alkyl, heteroaryl C _1-6 Alkyl radical, C _3-6 Cycloalkyl or C _3-6 Cycloalkyl radical C _1-6 Alkyl, each of which is optionally selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group;

d) Or R _1g And R _1h Optionally linked together such that they form, together with the carbon atom to which they are attached, a 3 to 6 membered cycloalkyl or heterocyclic ring, optionally selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (1), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group;

and T ₁ Selected from hydrogen, halogen, C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl), C _3-8 Cycloalkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, C _3-6 Cycloalkyl, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (A), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

(iv) Or R _1e And R _1f Are linked such that together with the nitrogen atom to which they are attached they form a mono-or bicyclic heterocyclic ring, optionally substituted by one or more substituents selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (1), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group;

any of alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (A), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group;

R _1b selected from hydrogen, cyano, halogen or C _1-3 An alkyl group;

R _1x selected from hydrogen, cyano, halogen or C _1-3 An alkyl group;

-L _2a -L _2b -Q ₂

wherein

L _2b absent or selected from O, S, SO ₂ 、N(R _n )、C(O)、C(O)O、OC(O)、C(O)N(R _n )、N(R _n )C(O)、N(R _n )C(O)N(R _o )、S(O) ₂ N(R _n ) Or N (R) _n )SO ₂ Wherein R is _n And R _o Each independently selected from hydrogen or C _1-2 An alkyl group; and is

Q ₂ Is hydrogen, cyano, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by a group selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, aminosulfonyl, C _1-4 Alkyl, NR _p R _q 、OR _p 、C(O)R _p 、C(O)OR _p 、OC(O)R _p 、C(O)N(R _p )R _q 、N(R _r )C(O)R _p 、S(O) _y R _p (wherein y is 0, 1)Or 2), SO ₂ N(R _p )R _q 、N(R _r )SO ₂ R _p Or (CH) ₂ ) _z NR _p R _q (wherein z is 1, 2 or 3) wherein R is _p And R _q Each independently selected from hydrogen or C _1-4 An alkyl group;

y is selected from:

wherein:

provided that R is _3a1 、R _3b1 、R _3i1 、R _3l1 、R _3o1 、R _3r1 、R _3a2 、R _3b2 、R _3i2 、R _3l2 、R _3o2 And R _3s1 Cannot be halogen when n =1 or when n =2 and the carbon atom to which it is attached to an oxygen or nitrogen atom;

or R _3a1 And R _3a2 、R _3b1 And R _3b2 、R _3c1 And R _3c2 、R _3d1 And R _3d2 、R _3e1 And R _3e2 、R _3f1 And R _3f2 、R _3g1 And R _3g2 、R _3h1 And R _3h2 、R _3i1 And R _3i2 、R _3j1 And R _3j2 、R _3k1 And R _3k2 、R _3l1 And R _3l2 、R _3m1 And R _3m2 、R _3n1 And R _3n2 、R _3o1 And R _3o2 、R _3p1 And R _3p2 、R _3q1 And R _3q2 Or R _3r1 And R _3r2 Or R _3s1 And R _3s2 May be linked such that they form together with the carbon atoms to which they are attached a spiro-fused C _3-4 Cycloalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, methyl, amino, cyano, and hydroxy;

n is 0, 1 or 2;

z is selected from:

wherein:

R ₄ selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and methyl);

R ₅ selected from hydrogen, halogenCyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and methyl);

R ₆ selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and methyl);

R ₈ 、R ₉ 、R ₁₀ and R ₁₁ Independently selected from hydrogen, NH ₂ Halogen, cyano, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-6 Alkyl, -CH ₂ OCH ₃ 、-CH ₂ SO ₂ CH ₃ 、-SO ₂ CH ₃ 、-NHC(O)CH ₃ and-C (O) NR _v1 R _v2 Wherein R is _v1 And R _v2 Independently selected from hydrogen and methyl; or

R ₉ And R ₁₀ May be linked together such that they form, together with the atoms to which they are attached, a fused 5-or 6-membered saturated or unsaturated ring system, or R ₁₀ And R ₁₁ May be linked together such that they form, together with the atoms to which they are attached, a fused 5-or 6-membered saturated or unsaturated ring system, wherein the fused 5-or 6-membered saturated or unsaturated ring system may optionally be selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ia R _1ja or-S (O) _0- ₂ R _1ia R _1ja Wherein R is substituted with one or more substituents of (1), wherein R is _1ia And R _1ja Is H or C _1-2 An alkyl group;

R ₇ and R _11N Independently selected from hydrogen, NH ₂ Halogen, cyano and C _1-6 An alkyl group;

R _Z1 and R _Z1a Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl radicals of which C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally substituted with one or more of halo, methyl, or methoxy;

R _Z2 And R _Z2a Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 An alkoxy group;

R _Zi1b selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 An alkoxy group;

R _Zi2e selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 An alkoxy group;

R _Y5N and R _Z2N Selected from hydrogen or C _1-4 An alkyl group;

R _Z9 selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

R _Z10 selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

R _Z11 selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

R _Z12 selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

R _Z13 selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

R _Z14 selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

R _Z15 selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

R _Z16 selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

A ₁ Selected from the group consisting of CR ₁₂ And N;

A ₂ selected from the group consisting of CR ₁₃ And N;

A ₅ selected from the group consisting of CR ₁₆ And N;

A ₆ selected from the group consisting of CR ₁₇ And N;

A ₇ selected from the group consisting of CR ₁₈ And N;

A ₈ selected from the group consisting of CR ₁₉ R ₂₀ And NR ₂₁ ；

R ₁₂ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and C) _1-4 Alkyl groups);

R ₁₆ and R ₁₈ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _3-4 Cycloalkyl, 3-to 4-membered heterocyclyl and C _3-4- A cycloalkoxy group;

R ₁₇ selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 HaloalkoxyBase, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon-linked), wherein m is an integer from 1 to 6- (OCH ₂ CH ₂ ) _m -OCH ₃ 、NR _q R _r Wherein R is _q And R _r Each independently of the other is hydrogen, C _1-5 Alkyl radical, C _3-6 Cycloalkyl, 3-to 6-membered carbon-linked heterocyclyl, or R _q And R _r Are linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring; wherein any C _1-5 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a substituent selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0- ₂ R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

R ₁₉ and R ₂₀ Selected from hydrogen, halogen, cyano and C _1-4 An alkyl group;

R ₂₂ and R ₂₃ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and methyl;

R ₂₈ and R ₂₉ Selected from hydrogen, halogen, methoxy and methyl;

R ₂₁ 、R ₂₄ and R ₃₀ Is hydrogen or C _1-4 An alkyl group.

Particular compounds of the invention include, for example, compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein each of the following and any related substituents have any of the meanings defined above or in any of paragraphs (1) to (193) below, unless otherwise indicated:

X，Y，Z，R _1a ，R _1b ，R _1c ，R _1d ，R _1e ，R _1f ，R _2a ，R _2b ，R _2c ，R _2d ，Q ₁ ，Q _2a ，Q _2b ，Q _2c ，Q _2d ，Q ₃ ，Q ₄ ，R _3a1 ，R _3a2 ，R _3b1 ，R _3b2 ，R _3c1 ，R _3c2 ，R _3d1 ，R _3d2 ，R _3e1 ，R _3e2 ，R _3f1 ，R _3f2 ，R _3g1 ，R _3g2 ，R _3h1 ，R _3h2 ，R _3i1 ，R _3i2 ，R _3j1 ，R _3j2 ，R _3k1 ，R _3k2 ，R _3l1 ，R _3l2 ，R _3m1 ，R _3m2 ，R _3n1 ，R _3n2 ，R _3o1 ，R _3o2 ，R _3p1 ，R _3p2 ，n，R ₄ ，R ₅ ，R _X5a ，R _X5b ，R ₆ ，R ₇ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _11N ，R ₁₂ ，R ₁₃ ，R ₁₆ ，R ₁₇ ，R ₁₈ ，R ₁₉ ，R ₂₀ ，R ₂₁ ，R ₂₂ ，R ₂₃ ，R ₂₄ ，R ₂₈ ，R ₂₉ ，R ₃₀ ，R _Z1 ，R _Z1a ，R _Z1b ，R _Z1c ，R _Z1d ，R _Z2 ，R _Z2a ，R _Z3a ，R _Zi1 b，R _Zi2e ，R _Z9 ，R _Z10 ，RZ ₁₁ ，R _Z12 ，R _Z13 ，R _Z14 ，R _Z15 ，R _Z16 ，A ₁ ，A ₂ ，A ₅ ，A ₆ ，A ₇ ，A ₈ ，A ₉ ，A ₁₁ ：

(1)Q ₁ selected from O, NH or N-C _1-4 An alkyl group.

(2)Q ₁ Selected from NH or N-C _1-4 An alkyl group.

(3)Q ₁ Selected from NH or N-CH ₃ 。

(4)Q ₁ Is NH.

(5)Q _2a Is CR _2a ；

(6)Q _2b Is CR _2b ；

(7)Q _2c Is CR _2c ；

(8)Q _2d Is CR _2d ；

(9)Q ₃ Is CR _1b ；

(10)Q ₄ Is CR _1x ；

(11) X is selected from:

wherein Q ₁ 、R _1a 、R _1b 、R _1x 、R _2a 、R _2b 、R _2c 、R _2d As defined herein.

(12) X is selected from:

wherein Q ₁ 、R _1a 、R _1b 、R _2a 、R _2b 、R _2c And R _2d As defined herein.

(13) X is selected from:

wherein Q ₁ 、R _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein.

(14) X is selected from:

wherein Q ₁ 、R _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein.

(15) X is:

wherein Q ₁ 、R _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein.

(16) X is:

wherein Q ₁ 、R _1a 、R _1b 、R _2a And R _2d As defined herein.

(17)R _1b 、R _2a 、R _2b 、R _2c And R _2d Each independently selected from hydrogen, C _1-2 Alkyl or halogen.

(18) X is selected from:

wherein Q ₁ And R _1a As defined herein.

(19) X is selected from:

wherein Q ₁ And R _1a As defined herein.

(20) X is selected from:

wherein Q ₁ And R _1a As defined herein.

(21) X is selected from:

wherein R is _1a As defined herein.

(22) X is selected from:

wherein R is _1a As defined herein.

(23)R _1a Selected from the group consisting of:

(i)C _1-4 alkyl optionally substituted by halogen, cyano, hydroxy, C _3-6 Cycloalkyl, C _1-4- Alkoxy radical, C _1-4 Haloalkoxy, aryl or heteroaryl substitution; or alternatively

(ii) A group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is an integer selected from 0, 1, 2 or 3;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a base compound,

(ii)C _1-6 alkyl, optionally selected from cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (1), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group; and wherein C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally further substituted with halogen, cyano, or hydroxy;

(iv) Or R _1c And R _1d Are linked together such that they form, together with the carbon atom to which they are attached, a 3 to 6 membered cycloalkyl or heterocyclic or spirocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (1), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group;

R _1e and R _1f Each independently selected from:

(i) Hydrogen (including deuterium);

(iii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 0, 1, 2, 3, 4, 5 or 6;

R _1g and R _1h Independently selected from:

a) Hydrogen;

b)C _1-6 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy;

c) aryl-C _1-6 Alkyl, heteroaryl C _1-6 Alkyl radical, C _3-6 Cycloalkyl or C _3-6 Cycloalkyl radical C _1-6 Alkyl, each of which is optionally selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (1), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; or

and T ₁ Selected from hydrogen, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl group), C _3-8 Cycloalkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each optionally selected from C _1-2 Alkyl radical、C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (1), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group;

(24)R _1a selected from the group consisting of:

(i)C _1-4 alkyl optionally substituted by halogen, cyano, hydroxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocyclyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, aryl or heteroaryl substitution; or

(ii) A group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a salt thereof,

(ii)C _1-3 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (1), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group; and wherein C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy;

(iv) Or R _1c And R _1d Are linked together such that they form, together with the carbon atom to which they are attached, a 3 to 5 membered cycloalkyl or heterocyclic ring or a spiro ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group;

R _1e and R _1f Each independently selected from:

(i) Hydrogen (including deuterium);

(ii)C _1-6 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

(iii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

Wherein:

q is 0, 1, 2 or 3;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or

b)C _1-3 Alkyl optionally substituted with one or more substituents selected from: a cyano group; oxo; a hydroxyl group; c _1-3 An alkoxy group; halogen; c _1-4 A haloalkoxy group; -O-C _3-4 Cycloalkyl radicals of which-O-C _3-4 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy; NR (nitrogen to noise ratio) _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is _1ca And R _1da Is H or C _1-2 Alkyl radical NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group;

c) Or R _1g And R _1h Optionally linked together such that they form, together with the carbon atom to which they are attached, a 3 to 6 membered cycloalkyl or heterocyclic ring, optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group;

and T ₁ Selected from hydrogen, halogen, C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl group), C _3-8 Cycloalkyl, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl radicalsOr a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, C _3-6 Cycloalkyl, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (1), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

(iv) Or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group;

any of which is alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (A), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group;

(25)R _1a is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is an integer selected from 1 or 2;

R _1c And R _1d Independently selected from:

(i) Hydrogen (including deuterium); or alternatively

(ii)C _1-3 Alkyl, optionally substituted by one or more radicals selected from cyano, oxo, hydroxy, C _1-3 Alkoxy, halogen, C _1-3 Haloalkoxy, -O-C _3-4 Cycloalkyl or NH ₂ Substituted with one or more substituents of (a); wherein-O-C _3-6 Cycloalkyl is optionally substituted by halogen, cyano or hydroxy,

(iii)C _3-4 cycloalkyl optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy or NR _1ca R _1da Substitution; and

(iv) Or R _1c And R _1d Are linked together such that they form, together with the carbon atom to which they are attached, a 3 to 5 membered cycloalkyl or heterocyclic ring or a spiro ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2- Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group;

R _1e and R _1f Each independently selected from:

(i) Hydrogen (including deuterium);

(ii)C _1-6 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NH ₂ Substituted with one or more substituents of (a);

(iii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 0, 1, 2 or 3;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or

b)C _1-6 Alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 Alkyl radical NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy;

c) Or R _1g And R _1h Optionally linked together such that they form, together with the carbon atom to which they are attached, a 3 to 6 membered cycloalkyl or heterocyclic ring, optionally selected from C _1-2 Alkyl radical, C _1-2- Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (1), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group;

and T ₁ Selected from hydrogen, halogen, C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl group), C _3-8 Cycloalkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, C _3-6 Cycloalkyl, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (A), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

(iv) Or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (1), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro-fused which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (1), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group;

any of alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (A), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

(26)R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a salt thereof,

(ii)C _1-3 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-3 Alkoxy, halogen, C _1-43 Haloalkoxy, -O-C _3-4 Cycloalkyl or NH ₂ Substituted with one or more substituents of (a); wherein-O-C _3-6 Cycloalkyl is optionally substituted by halogen, cyano or hydroxy,

(iii) Or R _1c And R _1d Are linked together such that they form, together with the carbon atom to which they are attached, a 3 to 5 membered cycloalkyl or heterocyclic ring or a spiro ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group;

R _1e selected from the group consisting of:

(i) Hydrogen (including deuterium);

(ii)C _1-3 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy and NH ₂ Substituted with one or more substituents of (a);

and R is _1f Selected from the group consisting of:

(i)C _1-6 alkyl, optionally substituted by one or more radicals selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy and NH ₂ Substituted with one or more substituents of (a);

(ii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1, 2 or 3;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or

b)C _1-6 Alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, haloElement, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (1), wherein R is _1ca And R _1da Is H or C _1-2 Alkyl radical NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano, or hydroxy;

c) Or R _1g And R _1h Optionally linked together such that they form, together with the carbon atom to which they are attached, a 3 to 4 membered cycloalkyl or heterocyclic ring, optionally selected from C _1-2 Alkyl radical, C _1-2- Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2- Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group;

and T ₁ Selected from hydrogen, halogen, C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl), C _3-8 Cycloalkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, C _3-6 Cycloalkyl, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (A), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro-fused which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group;

(27)R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a base compound,

(ii)C _1-3 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-3 Alkoxy, halogen, C _1-3 Haloalkoxy, -O-C _3-4 Cycloalkyl or NH ₂ Substituted with one or more substituents of (a); wherein-O-C _3-6 CycloalkanesOptionally substituted by halogen, cyano or hydroxy,

(iii) Or R _1c And R _1d Are linked together such that they form, together with the carbon atom to which they are attached, a 3 to 5 membered cycloalkyl or heterocyclic ring or a spiro ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 (ii) one or more substituents of haloalkoxy;

R _1e selected from:

(i) Hydrogen (including deuterium);

R _1f is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1, 2 or 3;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or

b)C _1-3 Alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Substituted by one or more substituents of cycloalkyl, wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano, or hydroxy;

c) Or R _1g And R _1h Optionally linked together such that they form, together with the carbon atom to which they are attached, a 3 to 4 membered cycloalkyl or heterocyclic ring, optionally selected from C _1-2 Alkyl radical, C _1-2- Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2- (ii) one or more substituents of haloalkoxy;

and T ₁ Selected from halogen, C _1-4 Alkyl radical, C _1-4 Halogenated alkyl, cyanogenRadical, hydroxyl radical, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl), C _3-8 Cycloalkyl, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2- Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, C _3-6 Cycloalkyl, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (1), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group;

any of which is alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (A), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

(28)R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a salt thereof,

(ii)C _1-3 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-3 Alkoxy, halogen, C _1-3 Haloalkoxy, -O-C _3-4 Cycloalkyl or NH ₂ Substituted with one or more substituents of (a); wherein-O-C _3-6 Cycloalkyl is optionally substituted by halogen, cyano or hydroxy,

(iii) Or R _1c And R _1d Are linked together such that they form, together with the carbon atom to which they are attached, a 3 to 5 membered cycloalkyl or heterocyclic ring or a spiro ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy;

R _1e selected from the group consisting of:

(i) Hydrogen (including deuterium);

R _1f is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1 or 2;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or

b)C _1-3 Alkyl, optionally selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, -O-C ₃ Substituted by one or more substituents of cycloalkyl, wherein-O-C ₃ Cycloalkyl is optionally substituted with halogen, cyano or hydroxy;

and T ₁ Is selected from C _1-4 Alkyl radical, C _3-8 Cycloalkyl, aryl, heterocyclyl, heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy or C _3-6 One or more substituents of cycloalkyl;

or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-2 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-2 Alkyl radical, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (1), wherein R is _1i And R _1j Is H or C _1-2 An alkyl group;

any of which is alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally substituted by a group selected from cyano a hydroxyl group,Halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (1), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

(29)R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium), or

(ii)C _1-3 Alkyl, optionally selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, -O-C ₃ One or more substituents of a cycloalkyl group;

R _1e selected from hydrogen (including deuterium) or C _1-2 An alkyl group; and is provided with

R _1f Is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1 or 2;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or alternatively

b)C _1-2 Alkyl, optionally substituted by one or more radicals selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy;

and T ₁ Is selected from C _1-4 Alkyl radical, C _3-8 Cycloalkyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2- Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy or C _3-6 Cycloalkyl substituted with one or more substituents;

or R _1e And R _1f Are linked such that together with the nitrogen atom to which they are attached they form a mono-or bicyclic heterocyclic ring, optionally substituted by one or more substituents selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy, and/or by R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-2 Alkyl radical, C _1-2- Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 (ii) one or more substituents of haloalkoxy; any of which is alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (A), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

(30)R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from hydrogen (including deuterium) or C _1-2 An alkyl group;

R _1f Is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1 or 2;

R _1g and R _1h Independently selected from hydrogen (including deuterium) or C _1-2 An alkyl group;

and T ₁ Is selected from C _1-4 Alkyl radical, C _3-4 Cycloalkyl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3- Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy or C _3-6 Cycloalkyl substituted with one or more substituents;

or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy, and/or by R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 (ii) one or more substituents of haloalkoxy; wherein any alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (A), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

(31)R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is 1;

R _1e selected from hydrogen (including deuterium) or C _1-2 An alkyl group; and is

R _1f Is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1 or 2;

and T ₁ Is selected from C _3-4 Cycloalkyl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2- Haloalkoxy or C _3-6 One or more substituents of cycloalkyl;

or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 Substituted with one or more substituents of haloalkoxy, and/or by R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro-fused which in turn is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 Substituted with one or more substituents of haloalkoxy, wherein any alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (A), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

(32)R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is 1;

R _1f Is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1;

and T ₁ Is selected from C _3-4 Cycloalkyl, heterocyclyl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy or C _3-6 One or more substituents of the cycloalkyl group are substituted,

wherein any alkyl or alkoxy is optionally further substituted with one or more substituents selected from cyano, hydroxy or halogen.

(33)R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is 1;

R _1c and R _1d Independently selected from hydrogen (including deuterium) or C _1-2 An alkyl group; and is provided with

R _1e And R _1f Are linked such that together with the nitrogen atom to which they are attached they form a mono-or bicyclic heterocyclic ring, optionally substituted by one or more substituents selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy, and/or by R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy.

(34)R _1a Is that

Wherein T is ₁ As defined herein.

(35)R _1a Is a group of the formula:

wherein T is ₁ Is selected from C _3-4 Cycloalkyl, heterocyclyl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy;

(36)R _1a selected from the group consisting of:

(37)R _1a selected from:

(38)R _1a selected from the group consisting of:

(39)R _1a selected from the group consisting of:

(40)R _1a selected from the group consisting of:

(40a)R _1a selected from:

(41)R _1a selected from the group consisting of:

(41a)R _1a the method comprises the following steps:

(41b)R _1a the method comprises the following steps:

(41c)R _1a the method comprises the following steps:

(42)R _1a the method comprises the following steps:

(43)R _1b selected from hydrogen,Halogen or C _1-2 An alkyl group.

(44)R _1b Is hydrogen.

(45)R _1x Selected from hydrogen, halogen or C _1-2 An alkyl group.

(46)R _1x Is hydrogen.

(47)R _2a 、R _2b 、R _2c And R _2d Independently selected from hydrogen, cyano, halogen or a group of the formula:

-L _2a -L _2b -Q ₂

wherein

L _2a Is absent or is optionally substituted by C _1-2 Alkyl or oxo substituted C _1-3 An alkylene group;

L _2b is absent or selected from O, S, N (R) _n )、C(O)、C(O)O、OC(O)、C(O)N(R _n )、N(R _n )C(O)、N(R _n )C(O)N(R _o ) Wherein R is _n And R _o Each independently selected from hydrogen or C _1-2 An alkyl group; and is

Q ₂ Is hydrogen, cyano, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by a substituent selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, aminosulfonyl, C _1-4 Alkyl, NR _p R _q 、OR _p 、C(O)R _p Wherein R is substituted with one or more substituents of (A), wherein R is _p And R _q Each independently selected from hydrogen or C _1-4 An alkyl group. (48) R is _2a 、R _2b 、R _2c And R _2d Independently selected from hydrogen, cyano, halogen or a group of the formula:

-L _2a -L _2b -Q ₂

wherein

L _2a Is absent or optionally substituted by C _1-2 Alkyl substituted C _1-3 An alkylene group;

L _2b is absent or selected from O, S, N (R) _n ) C (O); and is

Q ₂ Is hydrogen,Cyano radicals, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano and hydroxy.

(49)R _2a 、R _2b 、R _2c And R _2d Independently selected from hydrogen, cyano, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano and hydroxy.

(50)R _2a 、R _2b 、R _2c And R _2d Independently selected from hydrogen, cyano, halogen or C _1-3 An alkyl group.

(51)R _2a 、R _2b 、R _2c And R _2d Independently selected from hydrogen or halogen.

(52)R _2a 、R _2b 、R _2c And R _2d Is hydrogen.

(53)R _3a1 、R _3b1 、R _3c1 、R _3d1 、R _3e1 、R _3f1 、R _3g1 、R _3h1 、R _3i1 、R _3j1 、R _3k1 、R _3l1 、R _3m1 、R _3n1 、R _3o1 、R _3p1 、R _3q1 、R _3r1 And R _3s1 Independently selected from hydrogen, C _1-6 Alkyl radical, C _3-4 Cycloalkyl, hydroxy and halogen; and wherein C _1-6 Alkyl or C _3-4 Cycloalkyl is optionally substituted with one or more substituents selected from halogen, amino, cyano, and hydroxy; and R is _3a2 、R _3b2 、R _3c2 、R _3d2 、R _3e2 、R _3f2 、R _3g2 、R _3h2 、R _3i2 、R _3j2 、R _3k2 、R _3l2 、R _3m2 、R _3n2 、R _3o2 、R _3p2 、R _3q2 、R _3r2 And R _3s2 Is hydrogen;

(54)R _3a1 、R _3b1 、R _3c1 、R _3d1 、R _3e1 、R _3f1 、R _3g1 、R _3h1 、R _3i1 、R _3j1 、R _3k1 、R _3l1 、R _3m1 、R _3n1 、R _3o1 、R _3p1 、R _3q1 、R _3r1 and R _3s1 Independently selected from hydrogen and C _1-6 An alkyl group; and wherein C _1-6 Alkyl is optionally substituted with one or more hydroxy substituents;

(55)R _3a1 、R _3b1 、R _3c1 、R _3d1 、R _3e1 、R _3f1 、R _3g1 、R _3h1 、R _3i1 、R _3j1 、R _3k1 、R _3l1 、R _3m1 、R _3n1 、R _3o1 、R _3p1 、R _3q1 、R _3r1 and R _3s1 Independently selected from hydrogen and methyl; and wherein methyl is optionally substituted with one or more hydroxy substituents;

(56)R _3a1 、R _3b1 、R _3c1 、R _3d1 、R _3e1 、R _3f1 、R _3g1 、R _3h1 、R _3i1 、R _3j1 、R _3k1 、R _3l1 、R _3m1 、R _3n1 、R _3o1 、R _3p1 、R _3q1 、R _3r1 And R _3s1 Independently selected from hydrogen and methyl; and wherein methyl is substituted with a hydroxy substituent;

(57)R _3a2 、R _3b2 、R _3c2 、R _3d2 、R _3e2 、R _3f2 、R _3g2 、R _3h2 、R _3i2 、R _3j2 、R _3k2 、R _3l2 、R _3m2 、R _3n2 、R _3o2 、R _3p2 、R _3q2 、R _3r2 and R _3s2 Is hydrogen;

(58)R _3a1 and R _3a2 、R _3b1 And R _3b2 、R _3c1 And R _3c2 、R _3d1 And R _3d2 、R _3e1 And R _3e2 、R _3f1 And R _3f2 、R _3g1 And R _3g2 、R _3h1 And R _3h2 、R _3i1 And R _3i2 、R _3j1 And R _3j2 、R _3k1 And R _3k2 、R _3l1 And R _3l2 、R _3m1 And R _3m2 、R _3n1 And R _3n2 、R _3o1 And R _3o2 、R _3p1 And R _3p2 、R _3q1 And R _3q2 、R _3r1 And R _3r2 And R _3s1 And R _3s2 Is hydrogen.

(59)R _3a1 And R _3a2 、R _3b1 And R _3b2 、R _3c1 And R _3c2 、R _3d1 And R _3d2 、R _3e1 And R _3e2 、R _3f1 And R _3f2 、R _3g1 And R _3g2 、R _3h1 And R _3h2 、R _3i1 And R _3i2 、R _3j1 And R _3j2 、R _3k1 And R _3k2 、R _3l1 And R _3l2 、R _3m1 And R _3m2 、R _3n1 And R _3n2 、R _3o1 And R _3o2 、R _3p1 And R _3p2 And R _3q1 And R _3q2 、R _3r1 And R _3r2 And R _3s1 And R _3s2 Connected to form spiro-fused C _3-4 Cycloalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, amino, cyano and hydroxy.

(60) n is 0, 1 or 2;

(61) n is 1 or 2;

(62) n is 1;

(63) Y is

Wherein R is _3a1 、R _3a2 And n is as defined herein;

(64) Y is

Wherein n is as defined herein;

(65) Y is

Wherein R is _3b1 、R _3b2 And n is as defined herein;

(66) Y is

Wherein R is _3c1 、R _3c2 And n is as defined herein;

(67) Y is

Wherein R is _3d1 、R _3d2 And n is as defined herein;

(68) Y is

Wherein R is _3e1 、R _3e2 And n is as defined herein;

(69) Y is

(70) Y is

Wherein R is _3f1 、R _3f2 And n is as defined herein;

(71) Y is

Wherein R is _3g1 、R _3g2 And n is as defined herein;

(72) Y is

Wherein R is _3h1 、R _3h2 And n is as defined herein;

(73) Y is

Wherein R is _3i1 、R _3i2 And n is as defined herein;

(74) Y is

Wherein R is _3j1 、R _3j2 And n is as defined herein;

(75) Y is

Wherein R is _3k1 、R _3k2 And n is as defined herein;

(76) Y is

Wherein R is _3l1 、R _3l2 And n is as defined herein;

(77) Y is

Wherein R is _3m1 、R _3m2 And n is as defined herein;

(78) Y is

Wherein R is _3n1 、R _3n2 And n is as defined herein;

(79) Y is

Wherein R is _3o1 、R _3o2 And n is as defined herein;

(80) Y is

Wherein R is _3p1 、R _3p2 And n is as defined herein;

(81) Y is

Wherein R is _3q1 、R _3q2 And n is as defined herein;

(82) Y is

Wherein R is _3r1 、R _3r2 And n is as defined herein;

(83) Y is

Wherein R is _3s1 、R _3s2 And n is as defined herein;

(84) Y is selected from:

(85) Y is selected from:

wherein R is _3a1 、R _3a2 、R _3b1 、R _3b2 、R _3e1 、R _3e2 、R _3i1 、R _3i2 、R _3j1 And R _3j2 As defined herein.

(86) Y is selected from:

(87) Y is selected from:

(88) Y is selected from

(89) Y is

(90)R ₄ 、R ₅ And R ₆ Independently selected from hydrogen and halogen;

(91)R ₄ 、R ₅ 、R ₆ is hydrogen;

(92) When Z is

When then R is ₇ 、R ₉ And R _11N Independently selected from hydrogen, halogen and cyano;

(93) When Z is

When then R is ₇ 、R ₉ And R _11N Is hydrogen;

(94) When Z is

When then R is ₈ 、R ₉ 、R ₁₀ And R ₁₁ Independently selected from hydrogen, NH ₂ Halogen, cyano, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-6 Alkyl, -CH ₂ OCH ₃ 、-CH ₂ SO ₂ CH ₃ 、-SO ₂ CH ₃ 、-NHC(O)CH ₃ and-C (O) NR _v1 R _v2 Wherein R is _v1 And R _v2 Independently selected from hydrogen and methyl; or R ₉ And R ₁₀ May be linked together to form a fused 5-or 6-membered saturated or unsaturated ring system, or R ₁₀ And R ₁₁ May be linked together to form a fused 5 or 6 membered saturated or unsaturated ring system.

(95) When Z is

When then R is ₈ 、R ₉ 、R ₁₀ And R ₁₁ Independently selected from hydrogen, NH ₂ Halogen, cyano, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy and C _1-3 An alkyl group.

(95a) When Z is

When then R is ₈ Selected from hydrogen, cyano, -CH ₂ OCH ₃ 、-CH ₂ SO ₂ CH ₃ 、-SO ₂ CH ₃ 、-NHC(O)CH ₃ and-C (O) NR _v1 R _v2 Wherein R is _v1 And R _v2 Independently selected from hydrogen and methyl; r ₉ Is hydrogen; r is ₁₀ Selected from halogen, C _1-4 Alkoxy or C _1-4 A haloalkoxy group; and R is ₁₁ Is hydrogen.

(96) When Z is

When then R is ₈ Is hydrogen, cyano, -CH ₂ OCH ₃ 、-CH ₂ SO ₂ CH ₃ 、-SO ₂ CH ₃ 、-NHC(O)CH ₃ and-C (O) NR _v1 R _v2 Wherein R is _v1 And R _v2 Independently selected from hydrogen and methyl; r ₉ Is hydrogen; r is ₁₀ Is C _1-4 Alkoxy or C _1-4 A haloalkoxy group; and R is ₁₁ Is hydrogen.

(97) When Z is

When then R is ₈ Is hydrogen or cyano; r ₉ Is hydrogen; r ₁₀ Is C _1-4 An alkoxy group; and R is ₁₁ Is hydrogen.

(97a) When Z is

When then R is ₈ 、R ₉ And R ₁₁ Is hydrogen, and R ₁₀ Is methoxy.

(98) When Z is

When then R is ₈ 、R ₉ 、R ₁₀ And R ₁₁ Is hydrogen.

(99)R _Z1 And R _Z1a Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl radicals of which C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally substituted with one or more of halo, methyl, or methoxy;

(100)R _Z1 and R _Z1a Selected from hydrogen, C _1-2 Alkyl, cyano, halogen, C _1-2 Haloalkyl, C _1-2 Haloalkoxy, C _1-2 An alkoxy group;

(101)R _Z1 and R _Z1a Selected from hydrogen, C _1-2 Alkyl, cyano and halogen;

(102)R _Z1 And R _Z1a Is hydrogen;

(103)R _Z2 、R _Z2a 、R _Z3a 、R _Zi1b and R _Zi2e Independently selected from hydrogen, C _1-4 Alkyl, cyano, halogen or C _1-4 An alkoxy group;

(104)R _Z2 、R _Z2a 、R _Z3a 、R _Zi1b and R _Zi2e Independently selected from hydrogen, cyano or halogen;

(105)R _Z2 、R _Z2a 、R _Z3a 、R _Zi1b and R _Zi2e Is hydrogen;

(106)R _B5N 、R _Y5N 、R _Z2N and R _11N Selected from hydrogen or methyl;

(107)R _B5N 、R _Y5N 、R _Z2N and R _11N Is hydrogen;

(108)R _Z4 、R _Z5 、R _Z6 、R _Z7 、R _Z8 、R _Z9 、R _Z10 、R _Z11 、R _Z12 、R _Z13 、R _Z14 、R _Z15 and R _Z16 Independently selected from hydrogen, halogen and cyano;

(109)R _Z4 、R _Z5 、R _Z6 、R _Z7 、R _Z8 、R _Z9 、R _Z10 、R _Z11 、R _Z12 、R _Z13 、R _Z14 、R _Z15 and R _Z16 Independently selected from hydrogen and halogen;

(110)R _Z4 、R _Z5 、R _Z6 、R _Z7 、R _Z8 、R _Z9 、R _Z10 、R _Z11 、R _Z12 、R _Z13 、R _Z14 、R _Z15 、R _Z16 is hydrogen;

(111) It is appropriate that the concentration of the organic solvent,

when X is present ₆ Is A ₁ When, A ₁ Is CR ₁₂ ；

When X is present ₇ Is A ₂ When, A ₂ Is CR ₁₃ ；

B ₁ Is A ₅ Wherein A is ₅ Is CR ₁₆ ；

B ₂ Is A ₆ Wherein A is ₆ Is CR ₁₇ ；

Y ₂ Is A ₇ In which is CR ₁₈ ；

When X is present ₆ Is A ₈ When, A ₈ Is CR ₁₉ R ₂₀ ；

When X is present ₇ Is A ₉ When, A ₉ Is CR ₂₂ R ₂₃ ；

When X is present ₇ Is A ₁₁ When, A ₁₁ Is CR ₂₈ R ₂₉ ；

And wherein R ₁₂ 、R ₁₃ 、R ₁₆ 、R ₁₇ 、R ₁₈ 、R ₁₉ 、R ₂₀ 、R ₂₁ 、R ₂₂ 、R ₂₃ 、R ₂₈ And R ₂₉ As defined herein.

(112)R ₁₂ 、R ₁₃ 、R ₁₆ 、R ₁₉ 、R ₂₀ 、R ₂₁ 、R ₂₂ And R ₂₃ Independently selected from hydrogen, halogen, cyano and methyl;

(113)R ₁₂ 、R ₁₃ 、R ₁₆ 、R ₁₉ 、R ₂₀ 、R ₂₁ 、R ₂₂ and R ₂₃ Is hydrogen;

(114)R ₁₂ selected from hydrogen, halogen, cyano and C _1-4 An alkyl group;

(115)R ₁₂ selected from hydrogen and halogen;

(116)R ₁₂ selected from hydrogen and chlorine;

(117)R ₁₂ is hydrogen;

(118)R ₁₃ selected from hydrogen, halogen, cyano and methyl;

(119)R ₁₃ is hydrogen;

(120)R ₁₃ selected from hydrogen, methoxy and methyl;

(121)R ₁₆ and R ₁₈ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _1-4 Haloalkyl and C _1-4 A haloalkoxy group;

(122)R ₁₆ and R ₁₈ Selected from hydrogen, halogen, cyano and C _1-4 An alkyl group;

(123)R ₁₆ and R ₁₈ Selected from hydrogen and halogen;

(124)R ₁₆ and R ₁₈ Is hydrogen;

(125)R ₁₇ selected from hydrogen, halogen, cyano, C _1-5 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon-linked), wherein m is an integer from 1 to 6- (OCH ₂ CH ₂ ) _m -OCH ₃ 、NR _q R _r Wherein R is _q And R _r Each independently of the other is hydrogen, C _1-4 Alkyl radical, C _3-6 Cycloalkyl, 3-to 6-membered carbon-linked heterocyclyl, or R _q And R _r Linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring;

wherein any C _1-5 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally furtherOne step is selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group.

(126)R ₁₇ Selected from hydrogen, halogen, cyano, C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _1-2 Alkoxy radical, C _1-2 Haloalkoxy, C _2-3 Alkenyl radical, C _2-3 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon-linked), wherein m is an integer from 1 to 6- (OCH ₂ CH ₂ ) _m -OCH ₃ 、NR _q R _r Wherein R is _q And R _r Each independently is hydrogen, C _1-2 Alkyl, or R _q And R _r Are linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring;

wherein any C _1- Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a group selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group.

(127)R ₁₇ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon-bonded), - (OCH) ₂ CH ₂ ) _m -OCH ₃ (wherein m is 1, 2 or 3), NR _q R _r Wherein R is _q And R _r Each independently is hydrogen, C _1-4 An alkyl group; or R _q And R _r Are linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring;

wherein any C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a group selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen and C _1-2 One or more substituents of haloalkoxy.

(128)R ₁₇ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, -O-C _3-4 Cycloalkyl, heterocyclyl, - (OCH) ₂ CH ₂ ) _m -OCH ₃ (wherein m is 1, 2 or 3), NR _q R _r Wherein R is _q And R _r Each independently is hydrogen or C _1-2 An alkyl group;

wherein any C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, -O-C _3-4 Cycloalkyl, heterocyclyl systems optionally further selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen and C _1-2 One or more substituents of haloalkoxy.

(129)R ₁₇ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl and 5 or 6 membered aryl or heteroaryl; wherein any C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, 5-or 6-membered aryl or heteroaryl is optionally further selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen and C _1-2 One or more substituents of haloalkoxy.

(130)R ₁₇ Selected from hydrogen, halogen, C _1-4 Alkoxy radical, C _2-4 Alkynyl and 5 or 6 membered aryl or heteroaryl.

(131)R ₁₇ Selected from hydrogen, C _1-4 Alkoxy, bromo, ethynyl, and pyrazolyl.

(132)R ₂₈ And R ₂₉ Selected from hydrogen or halogen, methoxy and methyl;

(133)R ₂₈ and R ₂₉ Is hydrogen;

(134)R ₂₁ 、R ₂₄ and R ₃₀ Independently selected from hydrogen or methyl;

(135)R ₂₁ 、R ₂₄ and R ₃₀ Is hydrogen;

(136) Z is selected from

Wherein X ₂ 、X ₃ 、X ₄ 、X ₅ 、X ₆ 、X ₇ 、X ₈ And X ₉ As defined herein;

(137) Z is

Wherein X ₂ 、X ₄ 、X ₅ 、X ₆ 、X ₇ 、X ₈ And X ₉ As defined herein;

(138) Z is

X ₂ Is CR ₄ ：

X ₄ Is C or N;

X ₅ is CR ₅ ：

X ₆ Is A ₁ Wherein A is ₁ Is CR ₁₂

X ₇ Is A ₂ Wherein A is ₂ Is CR ₁₃

X ₈ Is N or CR ₆ ，

X ₉ Is N or C;

wherein R is ₄ 、R ₅ 、R ₆ 、R ₁₂ And R ₁₃ As defined herein;

(139) Z is

Wherein R is ₄ 、R ₅ 、R ₆ 、A ₁ And A ₂ As defined herein;

(140) Z is

(141) Z is

X ₂ Is CR ₄ ：

X ₄ Is N;

X ₅ is CR ₅ ：

X ₆ Is A ₁ Wherein A is ₁ Is CR ₁₂

X ₇ Is A ₂ Wherein A is ₂ Is CR ₁₃

X ₈ Is CR ₆ ，

X ₉ Is N or C;

wherein R is ₄ 、R ₅ 、R ₆ 、R ₁₂ 、R ₁₃ 、X ₇ 、X ₈ And X ₉ As defined herein;

(142) Z is

Wherein R is ₄ 、R ₅ 、R ₆ 、A ₁ And A ₂ As defined herein;

(143) Z is

Wherein B is ₁ 、B ₂ 、B ₃ 、B ₄ 、B ₅ 、B ₇ And B ₈ As defined herein;

(144) Z is:

wherein

B ₁ Is A ₅ Wherein A is ₅ Is N or CR ₁₆ ；

B ₂ Is A ₆ Wherein A is ₆ Is CR ₁₇

B ₃ Is N or CR _Z1 ；

B ₄ Is N or C;

B ₅ selected from the group consisting of CR _zi1b Or NR _B5N

B ₇ Is N, NR _Z2N Or CR _Z2 ；

B ₈ Selected from C or N;

wherein R is ₁₆ 、R ₁₇ 、R _Z1 、R _zi1b 、R _B5N 、R _Z2 As defined herein;

(145) Z is:

wherein

B ₁ Is A ₅ Wherein A is ₅ Is CR ₁₆ ；

B ₂ Is A ₆ Wherein A is ₆ Is CR ₁₇

B ₃ Is CR _Z1 ；

B ₄ Is N or C;

B ₅ selected from the group consisting of CR _zi1b Or NR _B5N

B ₇ Is N, NH or CR _Z2 ；

B ₈ Is C;

(146) Z is

Wherein A is ₅ 、A ₆ 、R _Z1 And R _Z2 As defined herein;

(147) Z is

Wherein A is ₅ 、A ₆ 、R _Z1 、R _Z2 Is R _Zi1b As defined herein;

(148) Z is

Wherein A is ₅ 、A ₆ 、R _Z1 、R _Z2N And R _Zi1b As defined herein;

(149) Z is:

wherein R is _Z1 、R _Z2 、R _Zi1b 、A ₅ And A ₆ As defined herein;

(150) Z is:

wherein R is _Z2 、A ₅ And A ₆ As defined herein;

(151) Z is:

wherein R is _Z1d 、R _Z2d And A ₆ As defined herein;

(152) Z is

Wherein Q ₇ 、Q ₈ 、Q ₉ 、Q ₁₀ And Q ₁₁ As defined herein;

(153) Z is

Wherein Q ₈ 、Q ₉ 、Q ₁₀ And Q ₁₁ As defined herein;

(154) Z is selected from:

wherein R is ₇ 、R ₈ 、R ₉ 、R ₁₀ And R ₁₁ As defined herein;

(155) Z is

Wherein R is ₈ 、R ₉ 、R ₁₀ And R ₁₁ As defined herein;

(156) Z is

Wherein:

R ₈ selected from hydrogen, cyano, -CH ₂ OCH ₃ 、-CH ₂ SO ₂ CH ₃ 、-SO ₂ CH ₃ 、-NHC(O)CH ₃ and-C (O) NR _v1 R _v2 Wherein R is _v1 And R _v2 Independently selected from hydrogen and methyl;

R ₁₀ selected from halogen, C _1-4 Alkoxy or C _1-4 A haloalkoxy group;

R ₉ and R ₁₁ As defined herein;

(157) Z is

Wherein R is ₈ Is hydrogen or cyano, and R ₁₀ Is C _1-4 An alkoxy group;

(157a) Z is

(158) Z is

(159) Z is

Wherein A is ₇ 、R _Y5N 、R _Z1a 、R _Z2a And R _Z3a As defined herein;

(160) Z is

Wherein R is ₄ 、R ₅ 、A ₈ And A ₉ As defined herein;

(161) Z is

Wherein R is ₄ 、R ₅ 、R ₆ 、A ₈ And A ₁₁ As defined herein;

(162) Z is

Wherein Q ₈ 、Q ₉ 、Q ₁₀ And Q _11a As defined herein;

(163) Z is

Wherein R is ₇ 、R ₉ And R _11N As defined herein;

(164) Z is

Wherein

X ₁ Is N or CR _Z9 ；

X ₂ Is CR ₄ ：

X ₃ Is N;

X ₄ is C;

X ₅ is CR ₅ ：

X ₆ Is A ₁ Wherein A is ₁ Is CR ₁₂

X ₇ Is A ₂ Wherein A is ₂ Is CR ₁₃

X ₈ Is N or CR ₆ ，

X ₉ Is N or C;

wherein R is _Z9 、R ₄ 、R ₅ 、R ₆ 、R ₁₂ And R ₁₃ As defined herein.

(165) Z is

Wherein

Y ₂ Is A ₇ Wherein A is ₇ Is CR ₁₈ ；

Y ₃ Is N or CR _Z1a ；

Y ₄ Is C or N

Y ₅ Is NR _Y5N ；

Y ₆ Is C-R _Zi2e Or N;

Y ₇ is CR _Z2a Or N;

Y ₈ is C or N;

Y ₉ is CR _Z3a Or N;

wherein R is ₁₈ 、R _z1a 、R _Y5N 、R _Zi2e 、R _Z2a And R _Z3a As defined herein;

(166) Z is

Wherein

Y ₂ Is A ₇ Wherein A is ₇ Is CR ₁₈ ；

Y ₄ Is C or N

Y ₅ Is NR _Y5N ；

Y ₆ Is C-R _Zi2e Or N;

Y ₇ is CR _Z2a Or N;

Y ₈ is C or N;

Y ₉ is CR _Z3a Or N;

(167) Z is:

wherein R is _Y5N 、R _Z1a 、R _Z2a 、R _Z3a And A ₇ As defined herein;

(168) Z is:

wherein R is _Z1a 、R _Z2a 、R _Z3a And A ₇ As defined herein;

(169) Z is:

wherein R is _Y5N 、R _Z2a 、R _Z3a 、R _Zi2e And A ₇ As defined herein;

(170) Z is:

wherein R is _Z2a 、R _Z3a 、R _Zi2e And A ₇ As defined herein;

(171) Z is

Wherein

Y ₂ Is A ₇ Wherein A is ₇ Is CR ₁₈ ；

Y ₄ Is N

Y ₅ Is C-R _Y5 ；

Y ₆ Is C-R _Zi2e ；

Y ₇ Is O or S;

Y ₈ is C;

Y ₉ is N;

wherein R is ₁₈ 、R _Y5 、R _Zi2e As defined herein;

(172) Z is:

wherein A is ₇ And R _Zi2e As defined herein;

(173) Z is:

wherein R is ₄ 、R ₅ 、R ₆ 、R _Z9 、R ₁₂ And R ₁₃ As defined herein;

(174) Z is:

wherein R is ₄ 、R ₅ 、R ₆ 、R ₁₉ 、R ₂₂ And R _Z9 As defined herein;

(175) Z is

(176) Z is:

wherein R is ₄ 、R ₅ 、R ₆ 、R ₁₂ 、R ₁₃ And R _Z9 As defined herein;

(177) Z is

Wherein Z ₁₀ 、Z ₁₁ 、Z ₁₂ 、Z ₁₃ 、Z ₁₄ 、Z ₁₅ And Z ₁₆ As defined herein;

(178) Z is

Wherein

Z ₁₀ Is CR _Z10 ，

Z ₁₁ Is N;

Z ₁₂ is CR _Z12 ；

Z ₁₃ Is CR _Z13 ；

Z ₁₄ Is N or CR _Z14 ；

Z ₁₅ Is N or CR _Z15 ；

Z ₁₆ Is CR _Z16 ；

Wherein R is _Z10 、R _Z12 、R _Z13 、R _Z14 、R _Z15 And R _Z16 As defined herein;

(179) Z is

Wherein

Z ₁₀ Is CR _Z10 ，

Z ₁₁ Is CR _Z10 Or N;

Z ₁₂ is CR _Z12 ；

Z ₁₃ Is CR _Z13 ；

Z ₁₄ Is N;

Z ₁₅ is N or CR _Z15 ；

Z ₁₆ Is CR _Z16 ；

(180) Z is:

wherein Z ₁₀ 、Z ₁₂ 、Z ₁₃ 、Z ₁₄ 、Z ₁₅ And Z ₁₆ As defined herein;

(181) Z is:

wherein Z ₁₃ 、Z ₁₄ 、Z ₁₅ And Z ₁₆ As defined herein;

(182) Z is:

(183) Z is:

wherein Z ₁₀ 、Z ₁₁ 、Z ₁₂ 、Z ₁₃ 、Z ₁₅ And Z ₁₆ As defined herein in the context of the present invention,

(184) Z is:

wherein R is _Z10a 、R _Z11a 、R _Z12a 、R _Z13a 、R _Z15a And R _Z16a As defined herein;

(185) Z is selected from:

wherein B is ₁ 、B ₂ 、B ₃ 、B ₄ 、B ₅ 、B ₇ 、B ₈ 、Y ₂ 、Y ₃ 、Y ₄ 、Y ₅ 、Y ₆ 、Y ₇ 、Y ₈ 、Y ₉ 、X ₁ 、X ₂ 、X ₃ 、X ₄ 、X ₅ 、X ₆ 、X ₇ 、X ₈ And X ₉ As defined herein;

(186) Z is selected from:

wherein:

A ₁ ，A ₂ ，A ₅ ，A ₆ ，A ₇ ，A ₈ ，A ₉ ，A ₁₁ ，R ₄ ，R ₅ ，R ₆ ，R ₇ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _11N ，R ₁₂ ，R ₁₃ ，R ₁₉ ，R ₂₂ ，R _Y5N ，R _Z1 ，R _Z2 ，R _z9 ，R _Z10 ，R _Z11 ，R _Z12 ，R _Z13 ，R _Z14 ，R _Z15 ，R _Z16 ，R _Z2a ，R _Z3a ，R _Z1a ，R _Zi1b and R _Zi2e As defined herein;

(187) Z is selected from:

wherein A is ₁ ，A ₂ ，A ₅ ，A ₆ ，A ₇ ，A ₈ ，A ₉ ，A ₁₁ ，R ₄ ，R ₅ ，R ₆ ，R ₇ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _11N ，R ₁₂ ，R ₁₃ ，R ₁₉ ，R ₂₂ ，R _Z1 ，R _Z2 ，R _z9 ，R _Z10 ，R _Z11 ，R _Z12 ，R _Z13 ，R _Z14 ，R _Z15 ，R _Z16 ，R _Z2a ，R _Z3a ，R _Z1a ，R _zi1b And R _Zi2e As defined herein;

(188) Z is selected from:

A ₁ ，A ₂ ，A ₅ ，A ₆ ，A ₇ ，A ₈ ，A ₉ ，A ₁₁ ，R ₄ ，R ₅ ，R ₆ ，R ₇ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _Y5N ，R _Z1 ，R _Z2 ，R _Z10 ，R _Z12 ，R _Z13 ，R _Z14 ，R _Z15 ，R _Z16 ，R _Z2a ，R _Z3a ，R _Z1a ，R _Zi1b and R _Zi2e As defined herein;

(189) Z is selected from:

wherein A is ₁ ，A ₂ ，A ₅ ，A ₆ ，A ₇ ，A ₈ ，A ₉ ，A ₁₁ ，R ₄ ，R ₅ ，R ₆ ，R ₇ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _Y5N ，R _Z1 ，R _Z2 ，R _Z10 ，R _Z12 ，R _Z13 ，R _Z14 ，R _Z15 ，R _Z16 ，R _Z2a ，R _Z3a ，R _Z1a ，R _Zi1b And R _Zi2e As defined herein.

(190) Z is selected from:

wherein A is ₁ ，A ₂ ，A ₅ ，A ₆ ，A ₇ ，A ₈ ，A ₉ ，A ₁₁ ，R ₄ ，R ₅ ，R ₆ ，R ₇ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _Y5N ，R _Z1 ，R _Z2 ，R _Z10 ，R _Z12 ，R _Z13 ，R _Z14 ，R _Z15， R _Z16 ，R _Z2a ，R _Z3a ，R _Z1a ，R _Zi1b And R _Zi2e As defined herein.

(191) Z is selected from:

wherein R is ₈ 、R ₁₀ 、R ₁₇ 、R ₁₈ And R _Z1 As defined herein.

(192) Z is selected from:

(193) Z is selected from:

suitably, a heteroaryl or heterocyclyl as defined herein is a monocyclic heteroaryl or heterocyclyl comprising one, two or three heteroatoms selected from N, O or S.

Suitably, the heteroaryl is a 5 or 6 membered aryl or heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

Suitably, the heterocyclyl is a 4, 5 or 6 membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S. Most suitably, the heterocyclyl group is a 5-or 6-membered ring containing one, two or three heteroatoms selected from N, O or S [ e.g. morpholinyl (e.g. 4-morpholinyl), oxetane, methyloxetane (e.g. 3-methyloxetane), pyrrolidone (e.g. pyrrolidin-2-one) ].

Suitably, aryl is phenyl.

In one embodiment, X is

Y is selected from:

and Z is selected from:

wherein:

(i)R _1a 、R _1b 、R _2a 、R _2b and R _2d As defined herein;

(ii)R _3a1 、R _3a2 、R _3b1 、R _3b2 、R _3i1 、R _3i2 、R _3j1 、R _3j2 and n is as defined herein; and is

(iii)A ₁ ，A ₂ ，A ₅ ，A ₆ ，A ₇ ，R ₄ ，R ₅ ，R ₆ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _Z1 ，R _Z2 ，R _Z10 ，R _Z12 ，R _Z13 ，R _Z14 ，R _Z15 ，R _Z16 ，R _Z2a ，R _Z3a ，R _Zi2e ，R _Zi1b And R _Z2 As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

Z is

Wherein:

(i)R _1a 、R _1b 、R _2a 、R _2b and R _2d As defined herein;

(ii)n、R _3a1 、R _3a2 、R _3j1 、R _3j2 as defined herein; and is provided with

(iii)A ₁ ，A ₂ ，A ₅ ，A ₆ ，A ₇ ，R ₄ ，R ₅ ，R ₆ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _Z1 ，R _Z2 ，R _Z2a ，R _Z3a ，R _Zi2e ，R _Zi1b As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

Z is

Wherein:

(i)R _1a 、R _1b 、R _2a 、R _2b and R _2d As defined herein;

(ii)n、R _3a1 and R _3a2 As defined herein; and is

In one embodiment:

x is

Y is

And Z is

Wherein:

(i)R _1a 、R _1b 、R _2a 、R _2b and R _2d As defined herein;

(ii)n、R _3j1 And R _3j2 As defined herein; and is provided with

(iii)A ₁ 、A ₂ 、A ₅ 、A ₆ 、A ₇ 、R ₄ 、R ₅ 、R ₆ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R _Z1 、R _Z2 、R _Z2a 、R _Z3a 、R _Zi2e 、R _Zi1b As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is provided with

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein;

(ii)n、R _3a1 and R _3a2 As defined herein; and is

(iii)A ₅ 、A ₆ 、R _Z1 And R _Z2 As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein;

(ii)n、R _3a1 and R _3a2 As defined herein; and is

(iii)A ₁ 、A ₂ 、R ₄ 、R ₅ And R ₆ As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is provided with

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein;

(ii)n、R _3a1 and R _3a2 As defined herein; and is provided with

(iii)A ₅ 、A ₆ 、R _Z1 、R _Zi1b And R _Z2 As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d Such as bookAs defined herein;

(ii)n、R _3a1 and R _3a2 As defined herein; and is provided with

(iii)A _Z6 、R _Z2e 、R _Z3e And R _Zi2e As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein;

(ii)n、R _3a1 and R _3a2 As defined herein; and is

(iii)A ₅ 、A ₆ 、R _Z1 And R _Z2 As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein;

(ii)n、R _3a1 and R _3a2 As defined herein; and is

(iii)A ₁ 、A ₂ 、R ₄ 、R ₅ And R ₆ As defined herein.

In one embodiment of the process of the present invention,

X is

Y is

And is

Z is

(i) Wherein R is _1a 、R _1b 、R _2a And R _2d As defined herein;

(ii)n、R _3a1 and R _3a2 As defined herein; and is provided with

(iii)A ₅ 、A ₆ 、R _Z1 、R _Zi1b And R _Z2 As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

(iv) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein;

(v)n、R _3a1 and R _3a2 As defined herein; and is provided with

(vi)A _Z6 、R _Z2e 、R _Z3e And R _Zi2e As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein;

(ii)n、R _3j1 and R _3j2 As defined herein; and is provided with

(iii)A ₅ 、A ₆ 、R _Z1 And R _Z2 As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

(i) Wherein R is _1a 、R _1b 、R _2a And R _2d As defined herein;

(ii)n、R _3j1 and R _3j2 As defined herein; and is

(iii)A ₅ 、A ₆ 、R _Z1 And R _Z2 As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein;

(ii)n、R _3j1 and R _3j2 As defined herein; and is

(iii)A ₁ 、A ₂ 、R ₄ 、R ₅ And R ₆ As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

(iv) Wherein R is _1a 、R _1b 、R _2a And R _2d As defined herein;

(v)n、R _3j1 and R _3j2 As defined herein; and is

(vi)A ₁ 、A ₂ 、R ₄ 、R ₅ And R ₆ As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein;

(ii)n、R _3j1 and R _3j2 As defined herein; and is

(iii)A ₅ 、A ₆ 、R _Z1 、R _Zi1b And R _Z2 As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined herein;

(ii)n、R _3j1 and R _3j2 As defined herein; and is

(iii)A ₅ 、A ₆ 、R _Z1 、R _Zi1b And R _Z2 As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is provided with

Z is

Wherein:

(i)R _1a 、R _1b 、R _2a 、R _2b and R _2d As defined herein;

(ii)n、R _3j1 and R _3j2 As defined herein; and is

(iii)A ₇ 、R _Z2a 、R _Z3a And R _Zi2e As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is provided with

Z is

Wherein:

(i)R _1a 、R _1b 、R _2a 、R _2b and R _2d As defined herein;

(ii)n、R _3j1 and R _3j2 As defined herein; and is provided with

(iii)A ₇ 、R _Z2a 、R _Z3a And R _Zi2e As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

And is

Z is

Wherein:

(iv)R _1a 、R _1b 、R _2a 、R _2b and R _2d As defined herein;

(v)n、R _3j1 and R _3j2 As defined herein; and is provided with

(vi)R ₈ 、R ₉ 、R ₁₀ And R ₁₁ As defined herein.

In one embodiment of the process of the present invention,

x is

Y is

Z is

Wherein:

(iv)R _1a 、R _1b 、R _2a 、R _2b and R _2d As defined herein;

(v)n、R _3a1 、R _3a2 、R _3j1 、R _3j2 as defined herein; and is provided with

(vi)R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ As defined herein.

In one embodiment:

when X is present ₆ Is A ₁ When, A ₁ Is CR ₁₂ ；

When X is present ₇ Is A ₂ When, A ₂ Is CR ₁₃ ；

B ₁ Is A ₅ Wherein A is ₅ Is CR ₁₆ ；

B ₂ Is A ₆ Wherein A is ₆ Is CR ₁₇ ；

Y ₂ Is A ₇ Wherein A is ₇ Is CR ₁₈ ；

When X is present ₆ Is A ₈ When, A ₈ Is CR ₁₉ R ₂₀ ；

When X is present ₇ Is A ₉ When, A ₉ Is CR ₂₂ R ₂₃ ；

When X is present ₇ Is A ₁₁ When, A ₁₁ Is CR ₂₈ R ₂₉ ；

In one embodiment: a. The ₁ Is CR ₁₂ ；A ₂ Is CR ₁₃ ；A ₅ Is CR ₁₆ ；A ₆ Is CR ₁₇ ；A ₇ Is CR ₁₈ ；A ₈ Is CR ₁₉ R ₂₀ ；A ₉ Is CR ₂₂ R ₂₃ ；A ₁₁ Is CR ₂₈ R ₂₉ (ii) a Wherein R is ₁₂ 、R ₁₃ 、R ₁₆ 、R ₁₇ 、R ₁₈ 、R ₁₉ 、R ₂₀ 、R ₂₁ 、R ₂₂ 、R ₂₃ 、R ₂₈ And R ₂₉ As defined herein.

In one embodiment:

(i)R ₄ ，R ₅ ，R _X5a ，R _X5b ，R _Y5 ，R ₆ ，R ₇ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _11a ，R _11b ，R ₂₂ ，R _22a ，R _23a ，R _Zi1b ，R _Zi2e ，R _Z9 ，R _Z10 ，R _Z11 ，R _Z12 ，R _Z12a ，R _Z13 ，R _Z14 ，R _Z15 and R _Z16 Independently selected from hydrogen, methyl, cyano or halogen; and is

R _B5N 、R _Y5N 、R _Z2N And R _11N Selected from methyl or hydrogen;

(ii)R _Z1 and R _Z1a Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl and-O-C _3-6 A cycloalkyl group;

(iii)R ₁₂ 、R ₁₃ 、R ₁₆ 、R ₁₈ 、R ₁₉ 、R ₂₀ 、R ₂₁ 、R ₂₂ 、R ₂₃ 、R ₂₄ and R ₃₀ Independently selected from hydrogen, halogen, cyano and methyl;

(iv)R ₁₇ selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl, - (OCH) wherein m is an integer of 1 to 6 ₂ CH ₂ ) _m -OCH ₃ 、NR _q R _r Wherein R is _q And R _r Each independently is hydrogen, C _1-4 Alkyl, or R _q And R _r Linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring; wherein any C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a substituent selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group.

(v)R ₂₁ 、R ₂₄ And R ₃₀ Independently selected from hydrogen or methyl;

(vi)R ₂₈ and R ₂₉ Selected from hydrogen or halogen, methoxy and methyl.

In one embodiment:

(i)R ₄ ，R ₅ ，R _X5a ，R _X5b ，R _Y5 ，R _B5N ，R _Y5N ，R ₆ ，R ₇ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _11a ，R _11b ，R _11N ，R _Z2 ，R _Z2N R _Z2a ，R _Z3a ，R _Zi1b ，R _Zi2e ，R _Z9 ，R _Z10 ，R _Z11 ，R _Z12 ，R _Z12a ，R _Z13 ，R _Z14 ，R _Z15 and R _Z16 Is hydrogen;

(ii)R _Z1 and R _Z1a Selected from hydrogen, cyano, halogen, C _1-2 Haloalkyl, C _1-2 Haloalkoxy, C _1-2 Alkoxy radical, C _3-6 Cycloalkyl and-O-C _3-6 A cycloalkyl group;

(iii)R ₁₂ 、R ₁₃ 、R ₁₆ 、R ₁₈ 、R ₁₉ 、R ₂₀ 、R ₂₁ 、R ₂₂ 、R ₂₃ 、R ₂₄ and R ₃₀ Is hydrogen;

(iv)R ₁₇ selected from hydrogen, halogen, cyano, C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _1-2 Alkoxy radical, C _1-2 Haloalkoxy, C _2-3 Alkenyl radical, C _2-3 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl, wherein m is an integer from 1 to 6- (OCH) ₂ CH ₂ ) _m -OCH ₃ 、NR _q R _r Wherein R is _q And R _r Each independently is hydrogen, C _1-2 Alkyl, or R _q And R _r Linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring; wherein any C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a substituent selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

(v)R ₂₁ 、R ₂₄ and R ₃₀ Is hydrogen;

(vi)R ₂₈ and R ₂₉ Is hydrogen.

Suitably, X is as defined in any of paragraphs (11) to (22) above. More suitably, X is as defined in paragraphs (14), (15), (16) or (22). Most suitably, X is as defined in paragraph (22).

Suitably, Q ₁ As defined in any one of paragraphs (1) to (4) above. Most suitably, Q ₁ As defined in paragraph (3) or (4).

Suitably, Q _2a As defined in paragraph (5).

Suitably, Q _2b As defined in paragraph (6).

Suitably, Q _2c As defined in paragraph (7).

Suitably, Q _2d As defined in paragraph (8).

Suitably, Q ₃ As defined in paragraph (9).

Suitably, Q ₄ As defined in paragraph (10).

Suitably, R _1a As defined in any one of the above paragraphs (23) to (42). Suitably, R _1a As defined in any of paragraphs (30) to (35) or (36) to (42). More suitably, R _1a As defined in any of paragraphs (32) to (35) or (40) to (42). Most suitably, R _1a Any one of paragraphs (40) to (42), for example as defined in paragraphs (40 a), (41 b), (41 c) or (42).

Suitably, R _1b As defined in any one of paragraphs (43) to (44). Most suitably, R _1b As defined in paragraph (44).

Suitably, R _1x As defined in any of paragraphs (45) or (46). Most suitably, R _1x As defined in paragraph (46).

Suitably, R _2a 、R _2b 、R _2c And R _2d As defined in any one of paragraphs (47) to (52) above. Most suitably, R _2a 、R _2b And R _2c As defined in paragraph (51) or (52).

Suitably, Y is as defined in any of paragraphs (63) to (89) above. Most suitably, Y is as defined in any of paragraphs (86), (87), (88) or (89).

Suitably, n is as defined in any of paragraphs (60) to (62) above. Most suitably, n is as defined in paragraph (62), i.e. n is 1.

Suitably, R _3a1 ，R _3b1 ，R _3c1 ，R _3d1 ，R _3e1 ，R _3f1 ，R _3g1 ，R _3h1 ，R _3i1 ，R _3j1 ，R _3k1 ，R _3l1 ，R _3m1 ，R _3n1 ，R _3o1 、R _3p1 、R _3q1 、R _3r1 And R _3s1 As defined in any one of paragraphs (53) to (56) and (58) to (59) above. Most suitably, R _3a1 ，R _3b1 ，R _3c1 ，R _3d1 ，R _3e1 ，R _3f1 ，R _3g1 ，R _3h1 ，R _3i1 ，R _3j1 ，R _3k1 ，R _3l1 ，R _3m1 ，R _3n1 ，R _3o1 ，R _2p1 ，R _3q1 ，R _3r1 And R _3s1 As in paragraphs (56) or (58)And (5) limiting.

Suitably, R _3a2 ，R _3b2 ，R _3c2 ，R _3d2 ，R _3e2 ，R _3f2 ，R _3g2 ，R _3h2 ，R _3i2 ，R _3j2 ，R _3k2 ，R _3l2 ，R _3m2 ，R _3n2 ，R _3o2 ，R _3p2 、R _3q2 、R _3r2 And R _3s2 As defined in any of paragraphs (57), (58) and (59) above. Most suitably, R _3a2 ，R _3b2 ，R _3c2 ，R _3d2 ，R _3e2 ，R _3f2 ，R _3g2 ，R _3h2 ，R _3i2 ，R _3j2 ，R _3k2 ，R _3l2 ，R _3m2 ，R _3n2 ，R _3o2 ，R _3p2 、R _3q2 、R _3r2 And R _3s2 As defined in paragraph (57) or (58) above.

Suitably, Z is as defined in any of paragraphs (136) to (193) above. More suitably, Z is as defined in paragraphs (187) to (193). Most suitably, Z is as defined in any of paragraphs (190) to (193).

Suitably, R ₄ 、R ₅ And R ₆ As defined in any one of paragraphs (90) and (91). Most suitably, R ₄ 、R ₅ And R ₆ As defined in paragraph (91), i.e. R ₄ 、R ₅ And R ₆ Is hydrogen.

Suitably, when Z is:

when the temperature of the water is higher than the set temperature,

then R is ₇ 、R ₉ And R _11N As defined in any of paragraphs (92) and (93) above. Most suitably, R ₇ 、R ₉ And R _11N As defined in paragraph (93).

Suitably, when Z is

When the temperature of the water is higher than the set temperature,

then R is ₈ 、R ₉ 、R ₁₀ And R ₁₁ As defined in any of paragraphs (94) to (98) above. More suitably, R ₈ 、R ₉ 、R ₁₀ And R ₁₁ As defined in any of the above paragraphs (95) to (98). Most suitably, R ₈ 、R ₉ 、R ₁₀ And R ₁₁ As defined in paragraph (97), (97 a) or (98).

Suitably, R _Z1 And R _Z1a As defined in any of paragraphs (99) to (102). Most suitably, R _Z1 And R _Z1a As defined in paragraph (102).

Suitably, R _Z2 、R _Z2a 、R _Z3a 、R _Zi1b And R _Zi2e As defined in any of paragraphs (103) to (105). Most suitably, R _Z2 、R _Z2a 、R _Z3a 、R _Z3e 、R _Zi1b And R _Zi2e As defined in paragraph (105).

Suitably, R _B5N 、R _Y5N 、R _Z2N And R _11N As defined in paragraph (106) or (107). Most suitably, R _B5N 、R _Y5N 、R _Z2N And R _11N As defined in paragraph (106).

Suitably, R _Z4 ，R _Z5 ，R _Z6 ，R _Z7 ，R _Z8 ，R _Z9 ，R _Z10 ，R _Z11 ，R _Z12 ，R _Z13 ，R _Z14 ，R _Z15 And R _Z16 As defined in any of paragraphs (108) to (110). Most suitably, R _Z4 ，R _Z5 ，R _Z6 ，R _Z7 ，R _Z8 ，R _Z9 ，R _Z10 ，R _Z11 ，R _Z12 ，R _Z13 ，R _Z14 ，R _Z15 And R _Z16 As defined in paragraph (110).

Suitably, A ₁ 、A ₂ 、A ₅ 、A ₆ 、A ₇ 、A ₈ 、A ₉ And A ₁₁ As defined in paragraph (111).

Suitably, R ₁₂ 、R ₁₃ 、R ₁₆ 、R ₁₉ 、R ₂₀ 、R ₂₁ 、R ₂₂ And R ₂₃ As defined in any of paragraphs (112) or (113) above. Most suitably, R ₁₂ 、R ₁₃ 、R ₁₆ 、R ₁₉ 、R ₂₀ 、R ₂₁ 、R ₂₂ And R ₂₃ As defined in paragraph (113).

Suitably, R ₁₂ As defined in any of the above paragraphs (114) to (117). Most suitably, R ₁₂ As defined in paragraph (117), i.e. R ₁₂ Is hydrogen.

Suitably, R ₁₃ As defined in any of paragraphs (118) to (120) above. Most suitably, R ₁₃ As defined in paragraph (119).

Suitably, R ₁₆ And R ₁₈ As defined in any of paragraphs (121) to (124) above. Most suitably, R ₁₆ And R ₁₈ As defined in paragraph (124), i.e. R ₁₆ And R ₁₈ Is hydrogen.

Suitably, R ₁₇ As defined in any of paragraphs (125) to (131) above. More suitably, R ₁₇ As defined in any one of paragraphs (128) to (131). Most suitably, R ₁₇ As defined in any of paragraphs (129) to (131).

Suitably, R ₂₈ And R ₂₉ As defined in any of paragraphs (132) to (133) above. Most suitably, R ₂₈ And R ₂₉ As defined in paragraph (133).

Suitably, R ₂₁ 、R ₂₄ And R ₃₀ As defined in any of paragraphs (134) to (135) above. Most suitably, R ₂₁ 、R ₂₄ And R ₃₀ As defined in paragraph (135).

Suitably, R ₄ ，R ₅ ，R _X5a ，R _X5b ，R ₆ ，R ₇ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _11N ，R _Z1 ，R _Z1a ，R _Z2 ，R _Z2a ，R _Z3a ，R _Zi1b ，R _Zi1c ，R _Zi2e ，R _Z9 ，R _Z10 ，R _Z11 ，R _Z12 ，R _Z13 ，R _Z14 ，R _Z15 And R _Z16 Independently selected from hydrogen or methyl. Most suitably, R ₄ ，R ₅ ，R _X5a ，R _X5b ，R ₆ ，R ₇ ，R ₈ ，R ₉ ，R ₁₀ ，R ₁₁ ，R _11N ，R _Z1 ，R _Z1a ，R _Z2 ，R _Z2a ，R _Z3a ，R _Zi1b ，R _Zi1c ，R _Zi2e ，R _Z9 ，R _Z10 ，R _Z11 ，R _Z12 ，R _Z13 ，R _Z14 ，R _Z15 And R _Z16 Is hydrogen.

In particular groups of the compounds of the invention or pharmaceutically acceptable salts thereof, Y is as defined in paragraph (63), i.e. the compounds have the structural formula (II) (sub-definition of formula (I)) shown below:

Of which X, R _3a1 、R _3a2 N and Z each have any of the meanings defined herein.

In one embodiment of the compound of formula (II):

x is as defined in any one of paragraphs (11) to (22) above;

R _3a1 as defined in any one of paragraphs (53) to (56) and (58) to (59) above;

R _3a2 as defined in any of paragraphs (57), (58) and (59) above;

n is as defined in any of paragraphs (60) to (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In one embodiment of the compound of formula (II):

x is as defined in paragraph (22) above;

R _3a1 as defined in paragraph (56) above;

R _3a2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In certain groups of compounds of formula (II):

x is as defined in paragraphs (20), (21) or (22) above, and R _1a As defined in any one of paragraphs (23) to (42) above;

R _3a1 as defined in paragraph (56) above;

R _3a2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In certain groups of compounds of formula (II):

x is as defined in paragraph (22) above, and R _1a As defined in any of paragraphs (36) to (42) above;

R _3a1 as defined in paragraph (56) above;

R _3a2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In certain groups of compounds of formula (II):

x is as defined in paragraph (22) above, and R _1a As defined in paragraph (32) or (35) above;

R _3a1 as defined in paragraph (56) above;

R _3a2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In one embodiment of the compound of formula (II):

x is as defined in paragraph (14) above;

R _3a1 as in paragraphs (53) to (56) and paragraph (58) above) Any one of (1) to (59);

R _3a2 as defined in any of paragraphs (57), (58) and (59) above;

n is as defined in any of paragraphs (60) to (62) above; and is

Z is as defined in any of paragraphs (142), (146), and (156) above.

In particular groups of the compounds of the invention or pharmaceutically acceptable salts thereof, Y is as defined in paragraph (73), i.e. the compounds have the structural formula (III) (sub-definition of formula (I)) shown below:

of which X, R _3i1 、R _3i2 N and Z each have any of the meanings defined herein.

In one embodiment of the compound of formula (III):

x is as defined in any one of paragraphs (11) to (22) above;

R _3i1 as defined in any one of paragraphs (53) to (56) and paragraphs (58) to (59) above;

R _3i2 as defined in any of paragraphs (57), (58) and (59) above;

n is as defined in any of paragraphs (60) to (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In one embodiment of the compound of formula (III):

x is as defined in paragraph (22) above;

R _3i1 as defined in paragraph (56) above;

R _3i2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In certain groups of compounds of formula (III):

x is as aboveIs as defined in paragraph (20), (21) or (22), and R _1a As defined in any one of paragraphs (23) to (42) above;

R _3i1 as defined in paragraph (56) above;

R _3i2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is provided with

Z is as defined in any of paragraphs (136) to (193) above.

In certain groups of compounds of formula (III):

x is as defined in paragraph (22) above, and R _1a As defined in any one of the above paragraphs (30) to (35) or (36) to (42);

R _3i1 As defined in paragraph (56) above;

R _3i2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In certain groups of the compounds of the invention, or pharmaceutically acceptable salts thereof, Y is as defined in paragraph (64), i.e., the compounds have the structural formula (IV) (a sub-definition of formula (I)) shown below:

wherein X, n and Z each have any of the meanings defined herein.

In one embodiment of the compound of formula (IV):

x is as defined in any one of paragraphs (11) to (22) above;

n is as defined in any of paragraphs (60) to (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In one embodiment of the compound of formula (IV):

x is as defined in paragraph (22) above;

n is as defined in paragraph (62) above; and is provided with

Z is as defined in any of paragraphs (136) to (193) above.

In certain groups of compounds of formula (IV):

n is as defined in paragraph (62) above; and is provided with

Z is as defined in any of paragraphs (136) to (193) above.

In certain groups of compounds of formula (IV):

x is as defined in paragraph (22) above, and R _1a As defined in any one of paragraphs (30) to (35) or (36) to (42) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In certain groups of the compounds of the invention, or pharmaceutically acceptable salts thereof, Y is as defined in paragraph (74), i.e., the compounds have the structural formula (V) (sub-definition of formula (I)) shown below:

of which X, R _3j1 、R _3j2 N and Z each have any of the meanings defined herein.

In one embodiment of the compound of formula (V):

x is as defined in any one of paragraphs (11) to (22) above;

R _3j1 as defined in any one of paragraphs (53) to (56) and (58) to (59) above;

R _3j2 as defined in any of paragraphs (57), (58) and (59) above;

n is as defined in any of paragraphs (60) to (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In one embodiment of the compound of formula (V):

x is as defined in paragraph (22) above;

R _3j1 as defined in paragraph (56) above;

R _3j2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In certain groups of the compounds of formula (V):

R _3j1 as defined in paragraph (56) above;

R _3j2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In certain groups of the compounds of formula (V):

R _3j1 as defined in paragraph (56) above;

R _3j2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In particular groups of the compounds of the invention or pharmaceutically acceptable salts thereof, X is as defined in paragraph (15), i.e. the compounds have the structural formula (VI) (sub-definition of formula (I)) shown below:

wherein R is _1a 、R _1b 、R _2a 、R _2b 、R _2d Y and Z each have any of the meanings defined herein.

In one embodiment of the compound of formula (VI):

Q ₁ as defined in any one of paragraphs (1) to (4);

R _1a as defined in any one of paragraphs (23) to (42) above;

R _1b as defined in any one of paragraphs (43) to (44) above;

R _2a 、R _2b And R _2d As defined in any of paragraphs (47) to (52) above;

y is as defined in any one of paragraphs (63) to (89) above; and is

Z is as defined in any of paragraphs (136) to (193) above.

In one embodiment of the compound of formula (VI):

Q ₁ as defined in any of paragraphs (3) or (4);

R _1a as defined in any one of paragraphs (30) to (35) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraphs (51) or (52);

y is as defined in paragraphs (86), (87), (88) or (89) above; and is

Z is as defined in any of paragraphs (186) to (193) above.

In one embodiment of the compound of formula (VI):

Q ₁ as defined in any of paragraphs (3) or (4);

R _1a as defined in any of paragraphs (38) to (42) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraphs (51) or (52);

y is as defined in paragraphs (86), (87), (88) or (89) above; and is provided with

Z is as defined in any of paragraphs (136) to (193) above.

In one embodiment of the compound of formula (VI):

Q ₁ as defined in paragraph (3) or (4);

R _1a as defined in any of paragraphs (38) to (42) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraphs (51) or (52);

Y is as defined in any one of paragraphs (85) to (89) above; and is

Z is as defined in any one of paragraphs (189) to (193) above.

In certain groups of compounds of formula (VI):

Q ₁ as defined in paragraph (4);

R _1a as defined in paragraph (32) or (35) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (52);

y is as defined in paragraph (89) above;

z is as defined in any of paragraphs (193) above.

In certain groups of compounds of formula (XI):

Q ₁ as defined in paragraph (4);

R _1a as defined in any of paragraphs (40 a), (41 b), (41 c) or (42) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (52);

y is as defined in paragraph (89) above; and is

Z is as defined in paragraph (193) above.

In certain groups of the compounds of the invention, or pharmaceutically acceptable salts thereof, X is as defined in paragraph (15) and Y is as defined in paragraph (63), i.e. the compounds have the structural formula (VII) (a sub-definition of formula (I)) shown below:

wherein R is _1a 、R _1b 、R _2a 、R _2b 、R _2d 、R _3a1 、R _3a2 N and Z each have any of the meanings defined herein.

In one embodiment of the compound of formula (VII):

Q ₁ as defined in any of paragraphs (1) to (4);

R _1a as defined in any one of paragraphs (23) to (42) above;

R _1b As defined in any one of paragraphs (43) to (44) above;

R _2a 、R _2b and R _2d As defined in any of paragraphs (47) to (52) above;

R _3a1 as defined in any one of paragraphs (53) to (56) and (58) to (59) above;

R _3a2 as defined in any of paragraphs (57), (58) and (59) above;

n is as defined in any of paragraphs (60), (61), and (62) above;

z is as defined in any of paragraphs (136) to (193) above.

In one embodiment of the compound of formula (VII):

Q ₁ as defined in any of paragraphs (3) or (4);

R _1a as defined in any one of paragraphs (30) to (35) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (51) or (52);

R _3a1 as defined in paragraph (56) above;

R _3a2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (186) to (191) above.

In one embodiment of the compound of formula (VII):

Q ₁ as defined in any of paragraphs (3) or (4);

R _1a as defined in any of paragraphs (38) to (42) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (51) or (52);

R _3a1 as defined in paragraph (56) above;

R _3a2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is provided with

Z is as defined in any of paragraphs (136) to (193) above.

In one embodiment of the compound of formula (VII):

Q ₁ as defined in any of paragraphs (3) or (4);

R _1a as defined in any of the above paragraphs (38) to (42);

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (51) or (52);

R _3a1 as defined in paragraph (56) above;

R _3a2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (186) to (191) above.

In one embodiment of the compound of formula (VII):

Q ₁ as defined in any of paragraphs (3) or (4);

R _1a as in the preceding paragraph(32) The compound as defined in (1) or (35);

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraphs (51) or (52);

R _3a1 as defined in paragraph (56) above;

R _3a2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in any of paragraphs (186) to (191) above.

In one embodiment of the compound of formula (VII):

Q ₁ as defined in any of paragraphs (3) or (4);

R _1a as defined in any of the above paragraphs (38) to (42);

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraphs (51) or (52);

R _3a1 As defined in paragraph (56) above;

R _3a2 as defined in paragraph (57) above;

n is as defined in paragraph (62) above; and is

Z is as defined in paragraph (193) above.

In certain groups of the compounds of the invention, or pharmaceutically acceptable salts thereof, X is as defined in paragraph (15) and Z is as defined in paragraph (146), i.e. the compounds have the structural formula (VIII) (sub-definition of formula (I)) shown below:

of which X, R _1a 、R _1b 、R _2a 、R _2b 、R _2d 、Y、A ₅ 、A ₆ 、R _Z1 And R _Z2 Each having any of the meanings defined herein.

In one embodiment of the compound of formula (VIII):

Q ₁ as defined in any of paragraphs (1) to (4);

R _1a as defined in any one of paragraphs (23) to (42) above;

R _1b as defined in any one of paragraphs (43) to (44) above;

R _2a 、R _2b and R _2d As defined in any of paragraphs (47) to (52) above;

y is as defined in any one of paragraphs (63) to (89) above;

R _Z1 as defined in any of paragraphs (99) to (102) above;

R _Z2 as defined in any of paragraphs (103) to (105) above;

A ₅ is CR ₁₆ And R is ₁₆ As defined in any of paragraphs (121) to (124) above; and is

A ₆ Is CR ₁₇ And R is ₁₇ As defined in any of paragraphs (125) to (131) above.

In one embodiment of the compound of formula (VIII):

Q ₁ as defined in paragraph (3) or (4);

R _1a As defined in any one of paragraphs (30) to (35) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (51) or (52);

y is as defined in any one of paragraphs (85) to (89) above; and is provided with

R _Z1 As defined in any of paragraphs (101) to (102) above;

R _Z2 as defined in any of paragraphs (104) to (105) above;

A ₅ is CR ₁₆ And R is ₁₆ As defined in any of paragraphs (123) to (124) above; and is

A ₆ Is CR ₁₇ And R is ₁₇ As defined in any of paragraphs (128) to (131) above.

In one embodiment of the compound of formula (VIII):

Q ₁ as defined in paragraph (3) or (4);

R _1a as defined in any of paragraphs (38) to (42) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (51) or (52);

y is as defined in any one of paragraphs (85) to (89) above; and is

R _Z1 As defined in any of paragraphs (101) to (102) above;

R _Z2 as defined in any of paragraphs (104) to (105) above;

A ₅ is CR ₁₆ And R is ₁₆ As defined in any of paragraphs (123) to (124) above; and is provided with

In certain groups of compounds of formula (VIII):

Q ₁ as defined in paragraph (4);

R _1a as defined in any of paragraphs (40 a), (41 b), (41 c) or (42) above;

R _1b As defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (52);

y is as defined in any of paragraphs (87), (88) or (89) above;

R _Z1 as defined in any of the above paragraphs (102);

R _Z2 as defined in paragraph (105) above;

A ₅ is CR ₁₆ And R is ₁₆ As defined in paragraph (124) above; and is

A ₆ Is CR ₁₇ And R is ₁₇ As defined in any of paragraphs (130) to (131) above.

In a specific group of the compound of formula (VIII):

Q ₁ as defined in paragraph (4);

R _1a as defined in paragraph (32) or (35) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (52);

y is as defined in any of paragraphs (87), (88) or (89) above;

R _Z1 as defined in any of the preceding paragraphs (102);

R _Z2 as defined in paragraph (105) above;

A ₅ is CR ₁₆ And R is ₁₆ As defined in paragraph (124) above; and is

A ₆ Is CR ₁₇ And R is ₁₇ As defined in any of the above paragraphs (130) to (131).

In certain groups of the compounds of the invention or pharmaceutically acceptable salts thereof, X is as defined in paragraphs (14), (15) or (16) and Z is as defined in paragraph (142), i.e. the compounds have the structural formula (IX) or (X) (a sub-definition of formula (I)) shown below:

wherein R is _1a 、R _1b 、R _2a 、R _2b 、R _2d 、Q ₁ 、Y、A ₁ 、A ₂ 、R ₄ 、R ₅ And R ₆ Each having any of the meanings defined herein.

In one embodiment of the compound of formula (IX):

Q ₁ as defined in any one of paragraphs (1) to (4);

R _1a as defined in any one of the above paragraphs (23) to (42)Defining;

R _1b as defined in any one of paragraphs (43) to (44) above;

R _2a 、R _2b and R _2d As defined in any one of paragraphs (47) to (52) above;

y is as defined in any one of paragraphs (63) to (89) above;

A ₁ is CR ₁₂ And R is ₁₂ As defined in any of paragraphs (112), (113) or (114) to (117) above;

A ₂ is CR ₁₃ And R is ₁₃ As defined in any of paragraphs (112), (113) or (118) to (120) above;

R ₄ as defined in paragraph (90) or (91) above;

R ₅ as defined in paragraph (90) or (91) above; and is

R ₆ As defined in paragraph (90) or (91) above.

In one embodiment of the compound of formula (IX):

Q ₁ as defined in paragraph (3) or (4);

R _1a as defined in any one of paragraphs (30) to (35) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraphs (51) or (52);

y is as defined in any one of paragraphs (85) to (89) above;

A ₁ is CR ₁₂ And R is ₁₂ As defined in any of paragraphs (114) to (117) above;

A ₂ is CR ₁₃ And R is ₁₃ As defined in paragraph (120) above;

R ₄ as defined in paragraph (91) above;

R ₅ as defined in paragraph (91) above; and is

R ₆ As defined in paragraph (91) above.

In one embodiment of the compound of formula (IX):

Q ₁ as defined in paragraph (3) or (4);

R _1a as defined in any of paragraphs (38) to (42) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraphs (51) or (52);

y is as defined in any one of paragraphs (85) to (89) above;

A ₂ is CR ₁₃ And R is ₁₃ As defined in paragraph (120) above;

R ₄ as defined in paragraph (91) above;

R ₅ as defined in paragraph (91) above; and is provided with

R ₆ As defined in paragraph (91) above.

In one embodiment of the compound of formula (IX):

Q ₁ as defined in paragraph (4);

R _1a as defined in any of paragraphs (40 a), (41 b), (41 c) or (42) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (52);

y is as defined in any of paragraphs (88) or (89) above;

A ₁ is CR ₁₂ And R is ₁₂ As defined in any of paragraphs (116) to (117) above;

A ₂ is CR ₁₃ And R is ₁₃ As defined in paragraph (120) above;

R ₄ as defined in paragraph (91) above;

R ₅ as defined in paragraph (91) above; and is

R ₆ As defined in paragraph (91) above.

In one embodiment of the compound of formula (IX):

Q ₁ As defined in paragraph (4);

R _1a as defined in paragraph (32) or (35) above;

R _1b as defined in paragraph (44) above;

R _2a and R _2d As defined in paragraph (52);

y is as defined in any of paragraphs (88) or (89) above;

A ₂ is CR ₁₃ And R is ₁₃ As defined in paragraph (120) above;

R ₄ as defined in paragraph (91) above;

R ₅ as defined in paragraph (91) above; and is

R ₆ As defined in paragraph (91) above.

In one embodiment of the compound of formula (X):

Q ₁ as defined in any of paragraphs (1) to (4);

R _1a as defined in any one of paragraphs (23) to (42) above;

R _1b as defined in any one of paragraphs (43) to (44) above;

R _2a and R _2d As defined in any one of paragraphs (47) to (52) above;

y is as defined in any one of paragraphs (63) to (89) above;

R ₄ as defined in paragraph (90) or (91) above;

R ₅ as defined in paragraph (90) or (91) above; and is

R ₆ As defined in paragraph (90) or (91) above.

In one embodiment of the compound of formula (X):

Q ₁ As defined in paragraph (3) or (4);

R _1a as defined in any of paragraphs (38) to (42) above;

R _1b as defined in paragraph (44) above;

R _2a and R _2d As defined in paragraphs (51) or (52);

y is as defined in any one of paragraphs (85) to (89) above;

A ₂ is CR ₁₃ And R is ₁₃ As defined in paragraph (120) above;

R ₄ as defined in paragraph (91) above;

R ₅ as defined in paragraph (91) above; and is

R ₆ As defined in paragraph (91) above.

In one embodiment of the compound of formula (X):

Q ₁ as defined in paragraph (4);

R _1a as defined in any of paragraphs (40 a), (41 b), (41 c) or (42) above;

R _1b as defined in paragraph (44) above;

R _2a and R _2d As defined in paragraph (52);

y is as defined in any of paragraphs (88) or (89) above;

A ₂ is CR ₁₃ And R is ₁₃ As defined in paragraph (120) above;

R ₄ as defined in paragraph (91) above;

R ₅ as defined in paragraph (91) above; and is

R ₆ As defined in paragraph (91) above.

In one embodiment of the compound of formula (X):

Q ₁ as defined in paragraph (4);

R _1a as defined in paragraph (32) or (35) above;

R _1b As defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (52);

y is as defined in any of paragraphs (88) or (89) above;

A ₂ is CR ₁₃ And R is ₁₃ As defined in paragraph (120) above;

R ₄ as defined in paragraph (91) above;

R ₅ as defined in paragraph (91) above; and is

R ₆ As defined in paragraph (91) above.

In certain groups of the compounds of the invention or pharmaceutically acceptable salts thereof, X is as defined in paragraph (15) and Z is as defined in paragraph (147), i.e. the compounds have the structural formula (XI) (a sub-definition of formula (I)) shown below:

of which X, R _1a 、R _1b 、R _2a 、R _2b 、R _2d 、Y、A ₅ 、A ₆ 、R _Z1 、R _Z2 And R _Zi1b Each having any of the meanings defined herein.

In one embodiment of the compound of formula (XI):

Q ₁ as defined in any one of paragraphs (1) to (4);

R _1a as defined in any one of paragraphs (23) to (42) above;

R _1b as defined in any one of paragraphs (43) to (44) above;

R _2a 、R _2b and R _2d As defined in any of paragraphs (47) to (52) above;

y is as defined in any one of paragraphs (63) to (89) above; and is

A ₅ Is CR ₁₆ And R is ₁₆ As defined in any of paragraphs (121) to (124) above;

A ₆ is CR ₁₇ And R is ₁₇ As defined in any of paragraphs (125) to (131) above;

R _Z1 As defined in any of paragraphs (99) to (102) above;

R _Z2 as defined in any of paragraphs (103) to (105) above; and is

R _Zi1b As defined in any of paragraphs (103) to (105) above;

in one embodiment of the compound of formula (XI):

Q ₁ as defined in paragraph (3) or (4);

R _1a as defined in any of the above paragraphs (38) to (42);

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraphs (51) or (52);

y is as defined in any one of paragraphs (85) to (89) above; and is

A ₅ Is CR ₁₆ And R is ₁₆ As defined in any of paragraphs (123) to (124) above;

A ₆ is CR ₁₇ And R is ₁₇ As defined in any of paragraphs (128) to (131) above;

R _Z1 as in paragraphs (101) to (102) above) Any one of the above limitations;

R _Z2 as defined in any of paragraphs (104) to (105) above; and is

R _Zi1b As defined in any of paragraphs (104) to (105) above.

In one embodiment of the compound of formula (XI):

Q ₁ as defined in paragraph (3) or (4);

R _1a as defined in any one of paragraphs (30) to (35) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraphs (51) or (52);

y is as defined in any one of paragraphs (85) to (89) above; and is

R _Z1 as defined in any of paragraphs (101) to (102) above;

R _Z2 as defined in any of paragraphs (104) to (105) above; and is

R _Zi1b As defined in any of paragraphs (104) to (105) above.

In certain groups of compounds of formula (XI):

Q ₁ as defined in paragraph (4);

R _1a as defined in any of paragraphs (40 a), (41 b), (41 c) or (42) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (52);

y is as defined in any of paragraphs (87), (88) or (89) above;

A ₅ is CR ₁₆ And R is ₁₆ Such as byAs defined in the preceding paragraph (124);

A ₆ is CR ₁₇ And R is ₁₇ As defined in any of paragraphs (130) to (131) above; and is

R _Z1 As defined in paragraph (102) above;

R _Z2 as defined in paragraph (105) above; and is provided with

R _Zi1b As defined in paragraph (105) above.

In certain groups of compounds of formula (XI):

Q ₁ as defined in paragraph (4);

R _1a as defined in paragraph (32) or (35) above;

R _1b as defined in paragraph (44) above;

R _2a 、R _2b and R _2d As defined in paragraph (52);

y is as defined in any of paragraphs (87), (88) or (89) above;

A ₅ is CR ₁₆ And R is ₁₆ As defined in paragraph (124) above;

R _Z1 As defined in paragraph (102) above;

R _Z2 as defined in paragraph (105) above; and is

R _Zi1b As defined in paragraph (105) above.

In particular groups of the compounds of the invention or pharmaceutically acceptable salts thereof, X is as defined in paragraph (16), i.e. the compounds have the structural formula (XII) (sub-definition of formula (I)) shown below:

of which X, R _1a 、R _1b 、R _2a 、R _2d Y and Z each have any one defined hereinMeaning.

In one embodiment of the compound of formula (XII):

Q ₁ as defined in any of paragraphs (1) to (4);

R _1a as defined in any one of paragraphs (23) to (42) above;

R _1b as defined in any one of paragraphs (43) to (44) above;

R _2a and R _2d As defined in any of paragraphs (47) to (52) above;

y is as defined in any one of paragraphs (63) to (89) above; and is provided with

Z is as defined in any of paragraphs (136) to (193) above.

In one embodiment of the compound of formula (XII):

Q ₁ as defined in paragraph (3) or (4);

R _1a as defined in any one of paragraphs (30) to (35) above;

R _1b as defined in paragraph (44) above;

R _2a and R _2d As defined in paragraph (51) or (52) above;

Z is as defined in any of paragraphs (189) to (193) above.

In one embodiment of the compound of formula (XII):

Q ₁ as defined in paragraph (3) or (4);

R _1a as defined in any of paragraphs (38) to (42) above;

R _1b as defined in paragraph (44) above;

R _2a and R _2d As defined in paragraphs (51) or (52);

y is as defined in any one of paragraphs (85) to (89) above; and is

Z is as defined in any of paragraphs (189) to (193) above.

In certain groups of compounds of formula (XII):

Q ₁ as defined in paragraph (4);

R _1a as defined in paragraph (32) or (35) above;

R _1b as defined in paragraph (44) above;

R _2a and R _2d As defined in paragraph (52);

y is as defined in paragraph (89) above;

z is as defined in any of paragraphs (193) above.

In certain groups of compounds of formula (XII):

Q ₁ as defined in paragraph (4);

R _1a as defined in any of paragraphs (40 a), (41 b), (41 c) or (42) above;

R _1b as defined in paragraph (44) above;

R _2a and R _2d As defined in paragraph (52);

y is as defined in paragraph (89) above; and is

Z is as defined in paragraph (193) above.

In particular groups of compounds of the invention, Z is as defined in paragraph (155), i.e. the compounds have the structural formula (XIII) shown below (sub-definition of formula (I)):

In one embodiment of the compound of formula (XII):

x is as defined in any one of paragraphs (11) to (22) above;

y is as defined in any one of paragraphs (63) to (89) above; and is

R ₈ 、R ₉ 、R ₁₀ And R ₁₁ As defined in any of paragraphs (94) to (98) above.

In one embodiment of the compound of formula (XIII):

x is as defined in paragraphs (14), (15), (16) or (22) above;

y is as defined in any one of paragraphs (85) to (89) above;

In one embodiment of the compound of formula (XIII):

x is as defined in paragraphs (14), (15), (16) or (22) above;

y is as defined in any of paragraphs (86), (87), (88) or (89);

R ₈ 、R ₉ 、R ₁₀ and R ₁₁ As defined in any of paragraphs (95 a) to (97) above.

In particular groups of compounds of formula (XIII):

x is as defined in paragraphs (14), (15), (16) or (22) above;

y is as defined in any of paragraphs (88) or (89);

in particular groups of compounds of formula (XIII):

x is as defined in paragraph (22) above;

y is as defined in paragraph (89);

R ₈ 、R ₉ 、R ₁₀ and R ₁₁ As defined in paragraph (96), (97) or (97 a).

Particular compounds of the invention include any of the compounds exemplified herein, or pharmaceutically acceptable salts thereof, and in particular any of the following:

N- ({ 2- [ (4,4-dimethylpiperidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ [ (3,3-difluorocyclobutyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ [ (1-hydroxycyclobutyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ [ (1-fluorocyclobutyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ [ (1-methylcyclopropyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- (2-azabicyclo [2.1.1] hex-2-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- (3-azabicyclo [3.1.1] heptan-3-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ [2- (hydroxymethyl) pyrrolidin-1-yl ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- (morpholinomethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (1-adamantylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- [ [2- (1-piperidinylmethyl) -1H-indol-6-yl ] methyl ] pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (4-fluoro-1-piperidinyl) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- [ [2- [ [ [ rac- (1S, 2S, 4S) -7-oxabicyclo [2.2.1] hept-5-en-2-yl ] methylamino ] methyl ] -1H-indol-6-yl ] methyl ] pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ [ (1-hydroxycyclopentyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- [ [2- [ [ [ rac- (1S, 2R, 4S) -7-oxabicyclo [2.2.1] hept-5-en-2-yl ] methylamino ] methyl ] -1H-indol-6-yl ] methyl ] pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (1-bicyclo [1.1.1] pentylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclobutylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ ({ bicyclo [2.2.1] heptan-2-yl } amino) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclopropylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- (2-azabicyclo [2.2.2] oct-2-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ [ (2,2-difluorocyclopropyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ ({ 3-Fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclohexylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ [ (1-hydroxycyclohexyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclopentylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclopentylmethyl amino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ [ (1-methoxycyclobutyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (isobutylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclohexylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclopropylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- [ [2- [ (prop-2-ynylamino) methyl ] -1H-indol-6-yl ] methyl ] pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (oxetan-2-ylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (2,2-dimethylpropylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (1-bicyclo [1.1.1] pentylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ [ (1S, 2S) -2-hydroxycyclopentyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ [ (1R, 2R) -2-hydroxycyclopentyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ [ (1S, 2R) -2-hydroxycyclopentyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ [ (1R, 2S) -2-hydroxycyclopentyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclopropylmethylamino) methyl ] -5-fluoro-1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclobutylmethylamino) methyl ] -5-fluoro-1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- [ [2- [ (2,2,2-trifluoroethylamino) methyl ] -1H-indol-6-yl ] methyl ] pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ N- (cyclobutylmethyl) acetylamino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- { [2- (piperidin-2-yl) -1H-indol-6-yl ] methyl } -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -3-fluoro-1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1-methyl-1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclobutylmethylamino) -dideutero-methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -1H-indazole-4-carboxamide N- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-pyrrolo [3,2-b ] pyridin-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- (1H-indol-6-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- (1H-indol-2-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- (indoxazin-2-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (6- { [4- (1H-indazol-4-yl) -1H-1,2,3-triazol-1-yl ] methyl } -1H-indol-2-yl) methyl ] cyclopropylamine

(1R, 2S) -2- [ [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamino ] cyclopentanol

N- [ [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methyl ] cyclopentylamine

N- (cyclopropylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine

1- [ [ [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamino ] methyl ] cyclobutanol

N- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine

N- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-b ] pyridin-2-yl ] methylamine

N- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methylamine

2- [1- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] triazol-4-yl ] pyrido [1,2-a ] pyrimidin-4-one

N- (cyclobutylmethyl) -1- [6- [ [4- (6-methoxyimidazo [1,5-a ] pyridin-8-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine

N- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) imidazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine

N- (cyclobutylmethyl) -1- [6- [ [3- (1H-indazol-4-yl) -1,2,4-

Diazol-5-yl]Methyl radical]-1H-indol-2-yl]Methylamine

N- [ [2- (2-azaspiro [3.3] heptan-2-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (benzylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- (3-azabicyclo [3.1.0] hex-3-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ [ cyclobutylmethyl (methyl) amino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-1,3-benzoxadiazol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (but-2-yn-1-yl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (3-cyclopropylprop-2-yn-1-yl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ ({ bicyclo [3.1.0] hex-6-yl } amino) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ ({ bicyclo [2.1.1] hex-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ ({ 3-methylbicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (3-Methylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (3-fluoroazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (azetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ 2-azaspiro [3.4] octan-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (3-hydroxyazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (3,3-dimethylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- [ (2- { [3- (2,2,2-trifluoroethoxy) azetidin-1-yl ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [3- (difluoromethyl) azetidin-1-yl ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (3-methoxyazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [3- (tert-butoxy) azetidin-1-yl ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- [ (2- { [3- (trifluoromethyl) azetidin-1-yl ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (3-ethoxy azetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ 2-azaspiro [3.5] nonan-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (2-methylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (3,3-dimethylpyrrolidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ 6-fluoro-2-azaspiro [3.3] heptan-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ 6,6-difluoro-2-azaspiro [3.3] heptan-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (3-cyclobutyl-azetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (3-cyclopropylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (3-tert-butylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (1-tert-butylcyclopropyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ [ (3-methylcyclobutyl) methyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- [ (2- { [ (2,3,3-trimethylbutan-2-yl) amino ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ ({ imidazo [1,2-a ] pyridin-2-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (3,3-diethylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- [ (2- { [ (pent-3-yn-1-yl) amino ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ 6-azaspiro [3.4] octan-6-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (2,2-dimethylpyrrolidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ octahydrocyclopenta [ c ] pyrrol-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ 5-azaspiro [2.4] heptan-5-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ ({ 3-methoxybicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- [ (2- { [ ({ spiro [2.2] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- ({ 2- [ ({ spiro [2.3] hex-1-yl } amino) methyl ] -1H-indol-6-yl } methyl) -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ ({ 3-cyanobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ 1-oxa-6-azaspiro [3.4] octan-6-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ 2-azaspiro [4.4] nonan-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (1-methylcyclopentyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- (hydroxymethyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (1-cyclobutylcyclopropyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- { [2- ({ [ (1-methylcyclobutyl) methyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

4-oxo-N- [ (2- { [ ({ spiro [2.3] hex-5-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ ({ [3- (fluoromethyl) bicyclo [1.1.1] pentan-1-yl ] methyl } amino) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (1- { 3-Fluorobicyclo [1.1.1] pentan-1-yl } ethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- ({ 2- [ (tert-butylamino) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

4- (1- { [2- ({ 2-azaspiro [3.3] heptan-2-yl } methyl) -1H-indol-6-yl ] methyl } -1H-1,2,3-triazol-4-yl) -1H-indazole

N- { [2- (2- { 2-azaspiro [3.3] heptan-2-yl } ethyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

({ 3-Fluorobicyclo [1.1.1] pentan-1-yl } methyl) ({ 6- [ (4- { imidazo [1,5-a ] pyridin-8-yl } -1H-1,2,3-triazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine

N- [ (2- { [ ({ 3-Fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -5-oxo-5H- [1,3] thiazolo [3,2-a ] pyrimidine-7-carboxamide

N- [ (2- { [ ({ bicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-b ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ ({ 3-Fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-b ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-pyrrolo [3,2-b ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ ({ 3-methylbicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-c ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-pyrrolo [3,2-c ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ ({ bicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-c ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ ({ 3-Fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-c ]182 yrin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H, 6H,7H,8H, 9H-pyrido [1,2-a ] pyrimidine-2-carboxamide

(cyclobutylmethyl) ({ 6- [ (4- { 1H-pyrrolo [2,3-b ] pyridin-5-yl } -1H-imidazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine

(cyclobutylmethyl) ({ 6- [ (4- { imidazo [1,5-a ] pyridin-8-yl } -1H-1,2,3-triazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine

N- [ (2- { [ (2,2-dimethylpropyl) amino ] methyl } -1H-indol-6-yl) methyl ] -1H-pyrrolo [2,3-b ] pyridine-5-carboxamide

N- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -1H-pyrrolo [2,3-b ] pyridine-5-carboxamide

(cyclobutylmethyl) ({ 6- [ (4- { 1H-pyrrolo [2,3-b ] pyridin-5-yl } -1H-1,2,3-triazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine

N- [ [2- (2-azabicyclo [2.2.1] heptan-2-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (3-fluoro-1-bicyclo [1.1.1] pentyl) methyl ] -1- [6- [ (4-imidazo [1,5-a ] pyridin-8-yltriazol-1-yl) methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methylamine

(cyclobutylmethyl) [ (6- { [1- (1H-indazol-4-yl) -1H-1,2,3-triazol-4-yl ] methyl } -1H-indol-2-yl) methyl ] amine

[ (3,3-difluorocyclobutyl) methyl ] [ (6- { [1- (1H-indazol-4-yl) -1H-1,2,3-triazol-4-yl ] methyl } -1H-indol-2-yl) methyl ] amine

(cyclobutylmethyl) [ (6- { [1- (isoquinolin-4-yl) -1H-1,2,3-triazol-4-yl ] methyl } -1H-indol-2-yl) methyl ] amine

(cyclobutylmethyl) ({ 6- [ (1- { imidazo [1,5-a ] pyridin-8-yl } -1H-1,2,3-triazol-4-yl) methyl ] -1H-indol-2-yl } methyl) amine

3- [1- ({ 2- [ ({ (bicyclo [1.1.1] pent-1-yl) methyl } amino) methyl ] -1H-indol-6-yl } methyl) -1H-1,2,3-triazol-4-yl ] -5-methoxy-2-pyridinecarbonitrile;

3- [1- ({ 2- [ ({ (3-fluorobicyclo [1.1.1] pent-1-yl) methyl } amino) methyl ] -1H-indol-6-yl } methyl) -1H-1,2,3-triazol-4-yl ] -5-methoxy-2-pyridinecarbonitrile;

5-methoxy-3- [1- ({ 2- [ ({ (3-methylbicyclo [1.1.1] pent-1-yl) methyl } amino) methyl ] -1H-indol-6-yl } methyl) -1H-1,2,3-triazol-4-yl ] -2-pyridinecarbonitrile;

3- {1- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -1H-1,2,3-triazol-4-yl } -5-methoxy-2-pyridinecarbonitrile;

3- {1- [ (2- { (6-aza-6-spiro [3.4] octyl) methyl } -1H-indol-6-yl) methyl ] -1H-1,2,3-triazol-4-yl } -5-methoxy-2-pyridinecarbonitrile;

3- [1- ({ 2- [ (4,4-dimethyl-1-piperidinyl) methyl ] -1H-indol-6-yl } methyl) -1H-1,2,3-triazol-4-yl ] -5-methoxy-2-pyridinecarbonitrile;

n- ((2- ((6-azaspiro [3.4] octan-6-yl) methyl) -1H-pyrrolo [3,2-c ] pyridin-6-yl) methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

3- (1- ((2- (((cyclobutylmethyl) amino) methyl) -1H-indol-6-yl) methyl) -1H-1,2,3-triazol-4-yl) -5-fluoromethanecarbonitrile;

1-cyclobutyl-N- ((6- ((4- (5-methoxypyridin-3-yl) -1H-1,2,3-triazol-1-yl) methyl) -1H-indol-2-yl) methyl) methylamine;

5-chloro-3- (1- ((2- (((cyclobutylmethyl) amino) methyl) -1H-indol-6-yl) methyl) -1H-1,2,3-triazol-4-yl) picolinonitrile;

2- ((6-azaspiro [3.4] octan-6-yl) methyl) -6- ((4- (imidazo [1,5-a ] pyridin-8-yl) -1H-1,2,3-triazol-1-yl) methyl) -1H-pyrrolo [3,2-c ] pyridine.

Additional compounds of the invention or pharmaceutically acceptable salts thereof include any of the following:

3- {1- [ (2- { (6-aza-6-spiro [3.4] octyl) methyl } -1H-indol-6-yl) methyl ] -1H-1,2,3-triazol-4-yl } -5-methoxy-2-pyridinecarbonitrile; and

3- [1- ({ 2- [ (4,4-dimethyl-1-piperidinyl) methyl ] -1H-indol-6-yl } methyl) -1H-1,2,3-triazol-4-yl ] -5-methoxy-2-pyridinecarbonitrile.

Particular compounds of the invention include any of the compounds exemplified herein or a pharmaceutically acceptable salt thereof, and in particular any of the following:

n- [ [2- [ [ (1-hydroxycyclobutyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ [ (1-fluorocyclobutyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (4,4-dimethyl-1-piperidinyl) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -1H-pyrrolo [2,3-b ] pyridine-5-carboxamide

N- (cyclobutylmethyl) -1- [6- [ [4- (1H-pyrazolo [4,3-c ] pyridin-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine

N- (cyclobutylmethyl) -1- [6- [ [4- (1H-pyrrolo [2,3-b ] pyridin-5-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine

N- [ [2- [ [ (3-fluoro-1-bicyclo [1.1.1] pentyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (3,3-difluorocyclobutyl) methyl ] -1- [6- [ [1- (1H-indazol-4-yl) triazol-4-yl ] methyl ] -1H-indol-2-yl ] methylamine

N- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -1H-indazole-4-carboxamide N- [ [2- [ [ (1-fluorocyclobutyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ [2- [ (cyclobutylmethylamino) methyl ] -3H-benzimidazol-5-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- (cyclobutylmethyl) -1- [6- [ [1- (4-isoquinolinyl) triazol-4-yl ] methyl ] -1H-indol-2-yl ] methylamine

N- [ [2- [ (2,2-dimethylpropylamino) methyl ] -1H-indol-6-yl ] methyl ] -1H-pyrrolo [2,3-b ] pyridine-5-carboxamide

N- [ [2- [ (cyclohexylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide.

The various functional groups and substituents making up the compound of formula (I) are generally chosen so that the molecular weight of the compound of formula (I) does not exceed 1000. More typically, the molecular weight of the compound will be less than 900, such as less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, and for example 550 or less.

Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, acid addition salts of the compounds of the invention which are sufficiently basic, for example with inorganic or organic acids, for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulphonic acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the invention which are sufficiently acidic are alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts), ammonium salts or salts with organic bases which provide a pharmaceutically acceptable cation, for example salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

Compounds that have the same molecular formula but differ in the nature or bonding order of their atoms or the spatial arrangement of their atoms are referred to as "isomers". Isomers in which the arrangement of atoms in space is different are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers" and those that are not superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, one pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the R-and S-order rules of Cahn and Prelog, or by the way in which molecules rotate the plane of polarized light, and are called dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers, respectively). The chiral compounds may exist as individual enantiomers or as mixtures thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures".

The compounds of the invention may have one or more asymmetric centers; thus, such compounds may be prepared as individual (R) -or (S) -stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include the individual enantiomers and mixtures, racemates or otherwise thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in chapter 4 of "Advanced Organic Chemistry", 4 th edition j. March, john Wiley and Sons, new York, 2001), for example by synthesis from optically active starting materials or by resolution of racemic forms. Some of the compounds of the present invention may have geometric isomeric centers (E-and Z-isomers). It is to be understood that the present invention encompasses all optical, diastereomeric and geometric isomers and mixtures thereof that have antiproliferative activity.

The invention also encompasses compounds of the invention as defined herein, which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including ¹ H、 ² H (D) and ³ h (T); c may be in any isotopic form, including ¹² C、 ¹³ C and ¹⁴ c; and O may be in any isotopic form, including ¹⁶ O and ¹⁸ o; and the like.

It will also be appreciated that certain compounds of formula (I) (and compounds of formulae (II), (III) and (IV)) may exist in solvated as well as unsolvated forms, such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antiproliferative activity.

It is also understood that certain compounds of formula (I) (and compounds of formulae (II), (III), and (IV)) may exhibit polymorphisms and the present invention encompasses all such forms having antiproliferative activity.

The compounds of formula (I) (and compounds of formulae (II), (III) and (IV)) may exist in many different tautomeric forms and reference to a compound of formula (I) includes all such forms. For the avoidance of doubt, when a compound may exist in one of several tautomeric forms, and only one is specifically described or shown, all others are still included in formula (I). Some examples of tautomeric forms include keto-, enol-, and enolate- (enolate-) forms, as for example in the following tautomeric pairs: keto/enol (exemplified below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thione/enethiol, and nitro/acid-nitro (aci-nitro).

The compounds of formula (I) comprising amine functions may also form N-oxides. The compounds of formula (I) comprising amine functions mentioned herein also include N-oxides. When a compound contains several amine functional groups, one or more than one nitrogen atom may be oxidized to form an N-oxide. Some specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, advanced Organic Chemistry by Jerry March, 4 th edition, wiley Interscience, pages. More specifically, N-oxides may be prepared by the process of l.w. ready (syn.comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example in an inert solvent such as dichloromethane.

The compounds of formula (I) may be administered in the form of prodrugs which break down in the human or animal body to release the compounds of the invention. Prodrugs can be used to alter the physical and/or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the present invention contain suitable groups or substituents to which property modifying groups can be attached. Some examples of prodrugs include in vivo cleavable ester derivatives that may be formed at a carboxy or hydroxy group in the compound of formula (I) and in vivo cleavable amide derivatives that may be formed at a carboxy or amino group in the compound of formula (I).

Thus, when obtained by organic synthesis, and when obtained in vivo in humans or animals by cleavage of a prodrug thereof, the present invention includes those compounds of formula I as defined hereinbefore. Thus, the invention includes those compounds of formula (I) which are produced by organic synthesis methods, as well as those compounds which are produced in the human or animal body by metabolism of a precursor compound, i.e. the compounds of formula (I) may be synthetically produced compounds or metabolically produced compounds.

Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) are those prodrugs which are, based on sound medical judgment, suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity.

Various forms of prodrugs have been described, for example in the following documents:

a)Methods in Enzymologyof 1 at42 volumePages 309 to 396, edited by k.widder, et al (Academic Press, 1985);

b) Design of Pro-drugs, edited by H.Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Burdgaard, chapter 5 of H.Burdgaard "Design and Application of Pro-drugs", pages 113 to 191 (1991);

d)H.Bundgaard,Advanced Drug Delivery Reviews,8,1-38(1992)；

e)H.Bundgaard,et al.,Journal of Pharmaceutical Sciences,77,285(1988)；

f)N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984)；

g) T.higuchi and v.stella, "Pro-Drugs as Novel Delivery Systems", a.c.s.symposium Series, volume 14; and

h) Roche (editors), "Bioreversible Carriers in Drug Design", pergamon Press,1987.

Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) having a carboxy group are, for example, in vivo cleavable esters thereof. In vivo cleavable esters of compounds of formula (I) containing a carboxy group are, for example, pharmaceutically acceptable esters which are cleaved in the human or animal body to yield the parent acid. Suitable pharmaceutically acceptable esters for the carboxyl group include C _1-6 Alkyl esters (e.g. methyl, ethyl and tert-butyl), C _1-6 Alkoxymethyl esters (e.g. methoxymethyl ester), C _1-6 Alkanoyloxymethyl esters (e.g. pivaloyloxymethyl ester, 3-phthalidyl ester), C _3-8 Cycloalkyl carbonyloxy-C _1-6 Alkyl esters (e.g. cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl ester), 2-oxo-1,3-dioxolylmethyl ester (2-oxo-1,3-dioxolymethyl ester) (e.g. 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl ester) and C _1-6 alkoxy-carbonyloxy-C _1-6 Alkyl esters (e.g., methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters).

Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) having a hydroxyl group are, for example, in vivo cleavable esters or ethers thereof. An in vivo cleavable ester or ether of a compound of formula (I) containing a hydroxy group is a pharmaceutically acceptable ester or ether which is cleaved, for example, in the human or animal body to yield the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic esters such as phosphate esters (including phosphoramide cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include C _1-10 Alkanoyl (e.g. acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl), C _1-10 Alkoxycarbonyl (e.g. ethoxycarbonyl), N- (C) _1-6 ) ₂ Carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl. Some examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4- (C) _1-4 Alkyl) piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for the hydroxy group include α -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) having a carboxy group are, for example, in vivo cleavable amides thereof, such as amides formed with: amines, e.g. ammonia, C _1-4 Alkylamines, e.g. methylamine, (C) _1-4 Alkyl radical) ₂ Amines, e.g. dimethylamine, N-ethyl-N-methylamine or diethylamine, C _1-4 alkoxy-C _2-4 Alkylamines, e.g. 2-methoxyethylamine, phenyl-C _1-4 Alkylamines such as benzylamine and amino acids such as glycine or esters thereof.

Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides from amino groups include, for example, amides formed with: c _1-10 Alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl. Some examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4- (C) _1-4 Alkyl) piperazin-1-ylmethyl.

The in vivo effect of the compound of formula (I) may be exerted in part by one or more metabolites formed in the human or animal body following administration of the compound of formula (I). As mentioned before, the in vivo effects of the compounds of formula (I) may also be exerted by the metabolism of the precursor compounds (prodrugs).

Although the invention may be directed to any compound or specified group of compounds defined herein by way of optional, preferred or suitable features or in terms of specific embodiments, the invention may also be directed to any compound or specified group of compounds which specifically excludes said optional, preferred or suitable features or embodiments.

Suitably, the present invention excludes any individual compound which does not have a biological activity as defined herein.

Synthesis of

The compounds of the present invention may be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

In the description of the synthetic methods described herein, as well as in any reference synthetic methods used to prepare starting materials, it is understood that one skilled in the art may select all proposed reaction conditions, including selection of solvents, reaction atmospheres, reaction temperatures, test duration experiments, and processing procedures (workup procedure).

Those skilled in the art of organic synthesis understand that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions used.

It will be appreciated that during the synthesis of the compounds of the invention in the methods defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents from undesirable reactions. The skilled chemist will understand when such protection is required and how such protecting groups are put in place and subsequently removed.

For some examples of protecting Groups, see one of the many general texts on this subject, e.g., the 'Protective Groups in Organic Synthesis' of Theodora Green (publisher: john Wiley & Sons). The protecting group may be removed by any convenient method described in the literature or known to the skilled chemist as being suitable for removal of the protecting group in question, such methods being selected so as to effect removal of the protecting group with minimal interference with groups elsewhere in the molecule.

Thus, if a reactant includes a group such as an amino, carboxyl, or hydroxyl group, it may be desirable to protect that group in some of the reactions mentioned herein.

For example, suitable protecting groups for amino or alkylamino are, for example, acyl (e.g., alkanoyl such as acetyl), alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), arylmethoxycarbonyl (e.g., benzyloxycarbonyl), or aroyl (e.g., benzoyl). The deprotection conditions for the above-mentioned protecting groups necessarily vary depending on the choice of the protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups or aroyl groups, may be removed, for example, by hydrolysis with a suitable base, such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by: hydrogenation is carried out under conditions of a catalyst, such as palladium on carbon, or by treatment with a Lewis acid, such as boron tris (trifluoroacetic acid). Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines, for example dimethylaminopropylamine, or with hydrazine.

Suitable protecting groups for hydroxy groups are, for example, acyl groups (e.g. alkanoyl groups such as acetyl, aroyl groups such as benzoyl), or arylmethyl groups such as benzyl. The deprotection conditions for the above protecting groups will necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups (e.g., alkanoyl or aroyl) may be removed, for example, by hydrolysis with a suitable base, such as an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide) or ammonia. Alternatively, arylmethyl groups (e.g., benzyl groups) can be removed, for example, by hydrogenation over a catalyst (e.g., palladium on carbon).

Suitable protecting groups for the carboxyl group are, for example, esterified groups, such as methyl or ethyl, which can be removed, for example, by hydrolysis with a base (e.g. sodium hydroxide); or for example, a tert-butyl group, which can be removed, for example, by treatment with an acid (e.g., an organic acid such as trifluoroacetic acid); or, for example, benzyl, which can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

Resins may also be used as protecting groups.

The method used to synthesize the compounds of formula I will vary depending on the nature of the variable group. Suitable methods for their preparation are further described in the accompanying examples.

Once a compound of formula I has been synthesized by any of the methods defined herein, the method may further comprise the additional steps of:

(i) Removing any protecting groups present;

(ii) Converting a compound of formula I into another compound of formula I;

(iii) To form a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or

(iv) Forming a prodrug thereof.

The resulting compound of formula I may be isolated and purified using techniques well known in the art.

Biological activity

The METTL3 enzyme and cellular assays described in the examples section that follows are useful for measuring the pharmacological effects of the compounds of the invention.

Although the pharmacological properties of the compounds of formula I vary with structural changes, the compounds of the invention were found to be active in these METTL3 assays, as expected.

Generally, the compounds of the invention exhibit an IC of 10 μ M or less in the METTL3 enzyme assay described herein ₅₀ While preferred compounds of the invention exhibit an IC of 5 μ M or less ₅₀ And most preferably the compounds of the invention exhibit an IC of 2 μ M or less ₅₀ 。

Suitably the compound of formula (I) has an activity of less than 10 μ M in the METTL3 cell assay described in the examples section, whereas preferred compounds of the invention exhibit an IC of 5 μ M or less ₅₀ And most preferably the compound exhibits an activity of 2 μ M or less.

Pharmaceutical composition

According to another aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, as hereinbefore defined, and one or more pharmaceutically acceptable excipients.

The compositions of the invention may be in a form suitable for: for oral use (e.g. as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g. as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g. as a finely divided powder or a liquid aerosol), for administration by insufflation (inhalation) (e.g. as a finely divided powder) or for parenteral administration (e.g. as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as a suppository for rectal administration).

The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, a composition for oral use may comprise, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

An effective amount of a compound of the invention for use in treatment is an amount sufficient to treat or prevent an autoimmune disease as referred to herein and/or to treat or prevent a proliferative disorder, slow its progression and/or alleviate the symptoms associated with the disorder and/or disease.

The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual being treated and the particular route of administration. For example, formulations for oral administration to humans typically comprise, for example, 0.5mg to 0.5g of active agent (more suitably 0.5 to 100mg, e.g. 1 to 30 mg) compounded with an appropriate and convenient amount of excipient, which may be from about 5% to about 98% by weight of the total composition.

The size of the dose of the compound of formula (I) for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

Where the compounds of the invention are to be used for therapeutic or prophylactic purposes, they are generally administered so as to receive a daily dose, if required in divided doses, in the range of, for example, 0.1mg/kg to 75mg/kg of body weight. When the parenteral route is used, lower doses will generally be administered. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range of, for example, 0.1mg/kg to 30mg/kg body weight is generally employed. Similarly, for administration by inhalation, a dose in the range of, for example, 0.05mg/kg to 25mg/kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Generally, a unit dosage form will contain from about 0.5mg to 0.5g of a compound of the invention.

Therapeutic uses and applications

The present invention provides compounds that function as inhibitors of METTL3 activity.

Accordingly, the present invention provides a method of inhibiting METTL3 activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

The invention also provides a method of treating a disease or disorder in which METTL3 activity is implicated in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof. Suitably, the disease or disorder in which METTL3 activity is implicated is cancer, such as lung cancer, renal cancer, solid organ cancer, pancreatic cancer or leukaemia, type 2 diabetes, neuropsychiatric behaviour disorders, infection (e.g. viral infection) or depression.

The present invention provides a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

The present invention provides a method of treating a proliferative disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

The present invention provides a method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof. Suitably, the cancer is lung cancer, kidney cancer, solid organ cancer, pancreatic cancer or leukemia, suitably AML leukemia or chronic myelogenous leukemia.

The present invention provides a method of treating leukemia comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

The present invention provides a method of treating AML leukemia comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

The present invention provides a method of treating an autoimmune disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof. Suitably, the autoimmune disease is colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis or dermatitis.

The present invention provides a method of treating a neurological disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

The present invention provides a method of treating an infectious disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

The present invention provides a method of treating an inflammatory disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

METTL3 inhibitors are also potentially useful therapeutic agents for the treatment of diseases associated with silent X chromosome reactivation (Patil et al, nature,2016Sep 15 (537 (7620): 369-373). It is therefore a potentially effective therapeutic agent for the treatment of Rett syndrome.

The present invention also provides a method of treating a disease associated with silent X chromosome reactivation, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

The present invention also provides a method of treating rett syndrome, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in therapy.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for use in the treatment of a proliferative disorder.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of cancer. In a specific embodiment, the cancer is a human cancer. Suitably, the cancer is lung cancer, kidney cancer, solid organ cancer, pancreatic cancer or leukemia, suitably AML leukemia or chronic myelogenous leukemia.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of leukemia.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of AML leukemia.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in inhibiting METTL3 activity.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of an autoimmune disease. Suitably, the autoimmune disease is colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis or dermatitis.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of a neurological disease.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of an infectious disease.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of an inflammatory disease.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition in which METTL3 activity is implicated. Suitably, the disease or condition in which METTL3 activity is implicated is cancer, for example lung cancer, renal cancer, solid organ cancer, pancreatic cancer or leukaemia, type 2 diabetes, neuropsychiatric behaviour disorder or depression.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of a disease associated with silent X-chromosome reactivation.

The present invention provides a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof for use in the treatment of rett syndrome.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for the treatment of human cancer. Suitably, the cancer is lung cancer, kidney cancer, solid organ cancer, pancreatic cancer or leukemia, suitably AML leukemia or chronic myelogenous leukemia.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of leukaemia.

The present invention provides the use of a compound as defined herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of AML leukemia.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an autoimmune disease. Suitably, the autoimmune disease is colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis or dermatitis.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological disease.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an inflammatory disease.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an infectious disease.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting METTL3 activity.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or condition in which METTL3 activity is implicated. Suitably, the disease or condition in which METTL3 activity is implicated is cancer, for example lung cancer, renal cancer, solid organ cancer, pancreatic cancer or leukaemia, type 2 diabetes, neuropsychiatric behaviour disorder or depression.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with silent X-chromosome reactivation.

The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of rett syndrome.

The term "proliferative disorder" is used interchangeably herein and relates to undesired excessive or abnormal cell proliferation, such as tumor growth or proliferative growth, whether in vitro or in vivo, which is undesirable or uncontrolled. Some examples of proliferative disorders include, but are not limited to, premalignant and malignant cell proliferation, including, but not limited to, malignancies and tumors, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., of connective tissue), and atherosclerosis. Any type of cell can be treated, including but not limited to lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

The antiproliferative effects of the compounds of the invention have particular application in the treatment of human cancers (by virtue of their inhibition of METTL3 activity).

Anti-cancer effects can result from one or more mechanisms including, but not limited to, modulation of cell proliferation, inhibition of angiogenesis (formation of new blood vessels), inhibition of metastasis (spread of tumor from its source), inhibition of invasion (spread of tumor cells into adjacent normal structures), or promotion of apoptosis (programmed cell death).

In a particular embodiment of the invention, the proliferative disorder to be treated is cancer.

Route of administration

The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the desired site of action).

Routes of administration include, but are not limited to, oral (e.g., by ingestion); transbuccal; under the tongue; transdermal (including, e.g., via patches, creams, etc.); transmucosal (including, e.g., through patches, creams, etc.); intranasally (e.g., by nasal spray); ocular (e.g., by eye drops); transpulmonary (e.g., by treatment using, e.g., inhalation or insufflation via an aerosol, e.g., through the mouth or nose); rectally (e.g., by suppository or enema); transvaginal (e.g., by pessary); parenterally, e.g., by injection, including subcutaneously, intradermally, intramuscularly, intravenously, intraarterially, intracardially, intrathecally, intraspinally, intracapsularly, subcapsularly, intraorbitally, intraperitoneally, intratracheally, subcuticularly, intraarticularly, subarachnoid, and intrasternally; by implanting a depot (depot) or depot (reservoir), for example subcutaneously or intramuscularly.

Combination therapy

The antiproliferative treatment defined above may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following classes of anti-neoplastic agents:

(i) Other antiproliferative/antineoplastic agents and combinations thereof for medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil (chlorembucil), busulfan, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine and antifolates), such as fluoropyrimidines like 5-fluorouracil and tegafur (tegafur), raltitrexed (polytrexed), methotrexate (methotrexate), cytarabine (cytisine arabine) and hydroxyurea (hydroxyurea)); antitumor antibiotics (e.g., anthracyclines) such as doxorubicin (adriamycin), bleomycin (bleomycin), doxorubicin (doxorubicin), daunorubicin (daunomycin), epirubicin (epirubicin), idarubicin (idarubicin), mitomycin-C (mitomycin-C), actinomycin (dactinomycin), and mithramycin (mithramycin)); antimitotic agents (for example vinca alkaloids (vinca alkaloids), such as vincristine (vinchristine), vinblastine (vinblastine), vindesine (vindesine) and vinorelbine (vinorelbine), and taxanes such as taxol and taxotere (taxotere) and polokinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin);

(ii) Cytostatic agents, for example antiestrogens (e.g. tamoxifen (tamoxifen), fulvestrant (fulvestrant), toremifene (toremifene), raloxifene (raloxifene), droloxifene (droloxifene) and iodoxyfene (iodoxyfene)), antiandrogens (e.g. bicalutamide), flutamide (flutamide), nilutamide (nilutamide) and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin (goserelin), leuprolide (cyproterone acetate)), LHRH antagonists or LHRH agonists (e.g. goserelin (goserelin)Relin (leuprorelin) and buserelin (buserelin)), progestins (e.g., megestrol acetate (megestrol acetate)), aromatase inhibitors (e.g., such as anastrozole (anastrozole), letrozole (letrozole), vorozole (vorozole) and exemestane (exemestane)), and 5 α -reductase inhibitors, e.g., finasteride (finasteride); (iii) Anti-invasive agents [ e.g. inhibitors of the c-Src kinase family, such as 4- (6-chloro-2,3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD 0530; international patent application WO 01/94341), N- (2-chloro-6-methylphenyl) -2- {6- [4- (2-hydroxyethyl) piperazin-1-yl]-2-methylpyrimidin-4-ylamino } thiazole-5-carboxamide (dasatinib, BMS-354825; J.Med.Chem.,2004,476658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors such as marimastat (marimastat), urokinase plasminogen activator receptor function inhibitor or heparanase antibody]；

(iv) Growth factor function inhibitors: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB 2 antibody trastuzumab [ Herceptin ] ^TM ]anti-EGFR antibody panitumumab (panitumumab), anti-erbB 1 antibody cetuximab (cetuximab) [ Erbitux, C225]And any growth factor or growth factor receptor antibody disclosed in stem et al (Critical reviews in oncology/haematology,2005, vol. 54, p. 11 to 29); such inhibitors also include tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD 1839), N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) -quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; an insulin growth factor family inhibitor; platelet-derived growth factor family inhibitors, such as imatinib (imatinib) and/or nilotinib (AMN 107) ) (ii) a Serine/threonine kinase inhibitors (e.g., ras/Raf signaling inhibitors, such as farnesyltransferase inhibitors, e.g., sorafenib (BAY 43-9006), tipifarnib (tipifarnib) (R115777), and lonafarnib (SCH 66336)), inhibitors of cell signaling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX 39459) and cyclin dependent kinase inhibitors, e.g., CDK2 and/or CDK4 inhibitors;

(v) Anti-angiogenic agents, e.g., agents that inhibit the action of vascular endothelial growth factor, [ e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin) ^TM ) And for example VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD 6474), vatalanib (vatalanib) (PTK 787), sunitinib (sunitinib) (SU 11248), axitinib (axitinib) (AG-013736), pazopanib (pazopanib) (GW 786034) and 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD 2171; example 240 in WO 00/47212) compounds such as those disclosed in International patent applications WO97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds which act by other mechanisms (e.g. tricarboxyaminoquinolines (linomides), inhibitors of integrin α v β 3 function and angiostatins) ]；

(vi) Vascular damaging agents such as Combretastatin (Combretastatin) A4 and compounds disclosed in International patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) Endothelin receptor antagonists such as zibotentan (zibotentan) (ZD 4054) or atrasentan (atrasentan);

(viii) Antisense therapies, such as those directed against the above listed targets, e.g., ISIS 2503 (anti-ras antisense);

(ix) Gene therapy methods, including, for example, methods of replacing aberrant genes (e.g., aberrant p53 or aberrant BRCA1 or BRCA 2), GDEPT (gene-directed enzyme prodrug therapy) methods (e.g., methods using cytosine deaminase, thymidine kinase, or bacterial nitroreductase), and methods of increasing a patient's tolerance to chemotherapy or radiation therapy (e.g., multidrug resistance gene therapy);

(x) Immunotherapeutic approaches including, for example, ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells (e.g., transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony stimulating factor), approaches to reduce T cell disability, approaches using transfected immune cells (e.g., cytokine-transfected dendritic cells), approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies; and

(xi) Agents for treating AML leukemia include, for example, cytarabine, FLT3 inhibitors, BCL2 inhibitors (e.g., venetoclax) or IDH1/2 inhibitors.

In a particular embodiment, the anti-proliferative treatment as defined above may involve conventional surgery or radiotherapy or chemotherapy in addition to the compound of the invention.

Such combination therapy may be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products employ the compounds of the present invention within the dosage ranges described above and other pharmaceutically active agents within their approved dosage ranges.

According to this aspect of the invention there is provided a combination comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, as defined above, and another anti-tumour agent, for use in the treatment of cancer (e.g. cancer involving a solid tumour).

According to this aspect of the invention there is provided a combination comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, as defined hereinbefore and any one of the anti-tumour agents listed hereinbefore, for use in the treatment of a proliferative disorder (e.g. a cancer involving a solid tumour).

In another aspect of the invention, there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in combination with another anti-neoplastic agent, optionally selected from one of the agents listed above.

Herein, when the term "combination" is used, it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention, "combination" means simultaneous administration. In another aspect of the invention, "combination" means administered separately. In another aspect of the invention, "combination" refers to sequential administration. In the case of continuous or separate application, the delay in applying the second component should not lose the combined benefits.

According to another aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent, optionally selected from one of those listed above, in combination with a pharmaceutically acceptable diluent or carrier.

In another embodiment, the invention relates to a therapeutic combination comprising a compound as defined herein and a further agent for the treatment of AML leukemia, e.g. cytarabine, a FLT3 inhibitor, a BCL2 inhibitor or an IDH1/2 inhibitor. Suitably, the agent for treating AML leukemia is a BCL2 inhibitor, e.g. venetocel.

Examples

The following abbreviations are used in the examples:

AIBN-azobisisobutyronitrile

DBU-1,8-diazabicyclo [5.4.0] undec-7-ene

DCE-dichloroethane

DCM-dichloromethane

DIBAL-diisobutylaluminum hydride

DIPEA-N-ethyl-N-isopropyl-propan-2-amine

DMAP-4-dimethylaminopyridine

DMF-dimethylformamide

DMSO-dimethyl sulfoxide

DPPA-diphenylphosphoryl azide

HATU- [ dimethylamino (triazolo [4,5-b ] pyridin-3-yloxy) methylene ] -dimethyl-ammonium; hexafluorophosphates

HPLC-high performance liquid chromatography

IPA-isopropyl alcohol

LCMS-liquid chromatography mass spectrometry

NBS-N-bromosuccinimide

NMP-N-methyl-2-pyrrolidone

Phase sep cartridge-Telos Phase separator 6mL

RBF-round bottom flask

RM-reaction mixture

RT-Retention time

STAB-sodium triacetoxyborohydride

T3P-propylphosphonic acid anhydride

TBAF-tetra-n-butylammonium fluoride

TEA-Triethylamine

TFA-trifluoroacetic acid

TFAA-trifluoroacetic anhydride

THF-tetrahydrofuran

The following methods were used in the examples:

LCMS method a refers to low pH analysis performed at a flow rate of 1.2 mL/min over 1.2 minutes using a mobile phase consisting of 5% to 100% gradient of 0.1% formic acid in MeCN in water. The stationary phase consisted of Kinetex Core-Shell C18,2.1 mm. Times.50mm, 5 μm. The experiment was run at 40 ℃.

LCMS method B refers to high pH analysis performed at a flow rate of 1.0 mL/min over 2.1 minutes using a mobile phase consisting of 2mM ammonium bicarbonate buffered to pH 10 in 5% to 100% gradient MeCN in water. The stationary phase consists of Phenomenex Gemini-NX C18, 2.0X 50mm,3 μm. The experiment was run at 40 ℃.

LCMS method C refers to high pH analysis performed at a flow rate of 0.6 mL/min over 5.8 minutes using a mobile phase consisting of 2mM ammonium bicarbonate buffered to pH 10 in 5% to 100% gradient MeCN in water. Stationary phase is formed by Waters

BEHTM C18, 2.1X 100mm,1.7 μm. Experiment is carried out inThe operation was carried out at 40 ℃.

LCMS method D refers to high pH analysis performed at a flow rate of 0.6 mL/min over 5.9 minutes using a mobile phase consisting of 2mM ammonium bicarbonate buffered to pH 10 in MeCN in a gradient of 5% to 100% in water. The stationary phase consists of Phenomenex Gemini-NX C18, 2.0X 100mm,3 μm. The experiment was run at 40 ℃.

LCMS method E refers to low pH analysis performed at a flow rate of 0.6 mL/min over 5.3 minutes using a mobile phase consisting of 5% to 100% gradient of 0.1% formic acid in MeCN in water. The stationary phase consists of Phenomenex Kinetix-XB C18,2.1mm x 100mm,1.7 μm. The experiment was run at 40 ℃.

LCMS method F refers to high pH analysis performed at a flow rate of 1.0 mL/min over 0.75 minutes using a mobile phase consisting of 2mM ammonium bicarbonate buffered to pH 10 in 5% to 100% gradient of MeCN in water. Stationary phase is formed by Waters

BEHTM C18, 2.1X 100mm, 1.7. Mu.m. The experiment was run at 40 ℃.

Method G refers to a low pH analysis performed at a flow rate of 0.8 mL/min over 3.00 minutes using a mobile phase consisting of 0.1% formic acid in water (pH = 2.70) in a 3% to 100% gradient of 0.1% formic acid in water acetonitrile (10). The stationary phase consisted of a C18, 50X 2.1mm,1.6 μm column. The experiment was run at 35 ℃.

Method H refers to high pH analysis performed at a flow rate of 0.5 mL/min over 3.0 minutes using a mobile phase consisting of 5mM ammonium bicarbonate (pH 7.35) in a gradient MeCN in water. The stationary phase consisted of C18, 50X 2.1mm,2.5 μm. The experiment was run at 35 ℃.

Method I refers to high pH analysis performed at a flow rate of 0.5 mL/min over 3.0 minutes using a mobile phase consisting of 5mM ammonium bicarbonate (pH 7.35) in a gradient MeCN in water. The stationary phase consisted of C18, 50X 2.1mm,2.5 μm. The experiment was run at 35 ℃.

Method J refers to the use of a mobile phase consisting of 2mM ammonium bicarbonate buffered to pH 10 in a gradient of 1% to 100% MeCN at 1m over 1.35 minHigh pH analysis at L/min flow rate. Stationary phase is formed by Waters

BEHTM C18.1X 30mm,1.7 μm. The experiment was run at 40 ℃.

Method K refers to low pH analysis performed at a flow rate of 0.6 mL/min over 5.4 minutes using a mobile phase consisting of 0.1% formic acid in water in a 5% to 100% gradient of 0.1% formic acid in acetonitrile to 0.1% formic acid in water. The stationary phase consisted of Phenomenex Kinetex Core-Shell C8X 2.1mm,2.6um (protected by a "safety guard" column). The experiment was run at 40 ℃.

Method L refers to low pH analysis performed at a flow rate of 0.9 mL/min over 1.1 minutes using a mobile phase consisting of 0.1% formic acid in water in a 5% to 100% gradient of 0.1% formic acid in acetonitrile to 0.1% formic acid in water. Stationary phase is formed by Waters

BEHTM C18.1X 50mm,1.7 μm. The experiment was run at 40 ℃.

Method M refers to low pH analysis performed at a flow rate of 1.2 mL/min over 2.25 minutes using a mobile phase consisting of 0.1% formic acid in water in a 5% to 100% gradient of 0.1% formic acid in acetonitrile to 0.1% formic acid in water. The stationary phase consists of Phenomenex Kinetex Core-Shell C8X 2.1mm,2.6 um. The experiment was run at 40 ℃.

LC04_ ABF3 refers to high pH analysis performed at a flow rate of 1.0 mL/min over 2.70 minutes using a mobile phase consisting of 5mM ammonium bicarbonate buffered to pH 10 in a gradient of 50% to 100% acetonitrile in water. Stationary phase is formed by Waters

C18 4.6X 50mm,3.5 μm. The experiment was run at 30 ℃.

LC04_ ABR2 refers to high pH analysis performed at a flow rate of 1.0 mL/min over 9.0 minutes using a mobile phase consisting of 5mM ammonium bicarbonate buffered to pH 10 in a gradient of 10% to 100% acetonitrile in water. Stationary phase is formed by Waters

BEH ^TM C18 4.6X 150mm,3.5 μm. The experiment was run at 30 ℃.

LC03_ ABR2 refers to high pH analysis performed at a flow rate of 0.5 mL/min over 3.0 minutes using a mobile phase consisting of 5mM ammonium bicarbonate buffered to pH 10 in a gradient of 3% to 100% acetonitrile in water. Stationary phase is formed by Waters

BEH ^TM C18 2.1X 50mm,2.5 μm. The experiment was run at 30 ℃.

UC02_ FAR1 refers to a low pH analysis performed at a flow rate of 0.8 mL/min over 3.00 minutes using a mobile phase consisting of 0.1% formic acid in water (pH = 2.70) in a 3% to 100% gradient of 0.1% formic acid in water acetonitrile (10. Stationary phase is formed by Waters

BEH ^TM C18 2.1X 50mm,2.5 μm. The experiment was run at 30 ℃.

The following preparative HPLC method was used in the examples:

preparation method a refers to low pH purification at a flow rate of 40 mL/min over 14.4 minutes using a mobile phase consisting of 10% to 95% gradient of 0.1% formic acid in MeCN in water. The stationary phase consisted of Waters Sunfire C18, 30X 100mm,10 μm.

Preparation method B refers to high pH purification at a flow rate of 40 mL/min over 10 minutes using a mobile phase consisting of 30% to 95% gradient of 0.2% ammonium hydroxide in MeCN in water. The stationary phase consisted of Waters XBridge C18 OBDTM, 30X 100mm,10 μm.

Intermediate 1: 4-oxopyrido [1,2-a ] pyrimidine-2-carboxylic acid

4-Oxopyrido [1,2-a ] pyrimidine-2-carboxylic acid methyl ester [ Tetrahedron (2014), 70 (17), 2761-2765] (3.94g, 19.3mmol) was dissolved in hydrogen chloride solution (8M, 7.5mL) at room temperature (exotherm was noted upon addition), and the mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature, and the precipitate was collected by filtration and dried under vacuum to give the title compound as a white solid (3.00g, 81%).

The method A comprises the following steps: LC-MS (electrospray): m/z =191.1 (M + H) ⁺ RT =0.32 min

Example 1: n- ({ 2- [ (4,4-dimethylpiperidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

Step 1:2- (4,4-dimethylpiperidine-1-carbonyl) -1H-indole-6-carbonitrile

HATU (809mg, 2.13mmol) was added to a mixture of 6-cyano-1H-indole-2-carboxylic acid (330mg, 1.77mmol) and DIPEA (1.5ml, 8.86mmol) in DMF (26 mL), the mixture was stirred at ambient temperature for 5 min, followed by 4,4-dimethylpiperidine hydrochloride (292mg, 1.95mmol) and the mixture was stirred at ambient temperature for 1H. The mixture was washed with EtOAc and H ₂ O extraction, layers were separated, the mixture was extracted with EtOAc (3X 10 mL), and the organic layer was washed with brine, over MgSO ₄ Dried and concentrated. Purification by basic reverse phase HPLC gave the title compound as a yellow solid (100mg, 20%).

The method A comprises the following steps: LC-MS (electrospray): m/z =281.95 (M + H) ⁺ RT =1.20 min

And 2, step: [2- [ (4,4-dimethyl-1-piperidinyl) methyl ] -1H-indol-6-yl ] methylamine

Lithium aluminum hydride (2M in THF, 0.22mL, 0.44mmol) was added to a solution of 2- (4,4-dimethylpiperidine-1-carbonyl) -1H-indole-6-carbonitrile (100mg, 0.355mmol) in anhydrous THF (2 mL) at 0 deg.C. The mixture was stirred at 0 ℃, then warmed to room temperature and stirred for 1 hour. Additional lithium aluminum hydride (2M in THF, 0.22ml, 0.44mmol) was added and the mixture was stirred at ambient temperature for 67 hours. The reaction was cooled to 0 ℃ and quenched with H ₂ O (2 mL), naOH (1M, 2mL) and H ₂ O (6 mL) was treated dropwise. The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with THF. The filtrate was concentrated and purified by acidic reverse phase chromatography to give the title compound (86mg, 89%) as a yellow solid.

The method A comprises the following steps: LC-MS (electrospray): m/z =272.1 (M + H) ⁺ RT =0.31 min

And step 3: n- ({ 2- [ (4,4-dimethylpiperidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

HATU (80mg, 0.210mmol) was added to 4-oxopyrido [1,2-a]To a mixture of pyrimidine-2-carboxylic acid intermediate 1 (60%, 61mg, 0.19mmol) and DIPEA (0.15mL, 0.88mmol) in DMF (2.6 mL) was stirred at ambient temperature for 5 minutes, followed by addition of [2- [ (4,4-dimethyl-1-piperidinyl) methyl]-1H-indol-6-yl]Methylamine (48mg, 0.18mmol) and the mixture was stirred at ambient temperature for 1 hour. Additional HATU (45 mg) was added and stirring continued for 2 h. The mixture was washed with EtOAc and H ₂ Partition between O, separate the layers, and extract the mixture with EtOAc (3 × 10 mL). The organic layer was washed with brine, over MgSO ₄ Dried and concentrated under vacuum. The crude material was purified by preparative HPLC (method B) to give the title compound as a white solid (4.0 mg, 5.1%).

The method B comprises the following steps: LC-MS (electrospray): m/z＝444.3(M+H) ⁺ RT =4.59 minutes

Example 2: n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

Step 1: 3-amino-4- (3,3-diethoxyprop-1-yn-1-yl) benzonitrile

To a solution of 3-amino-4-iodobenzonitrile (8.00g, 32.8mmol) in anhydrous THF (40 mL) and triethylamine (80mL, 0.574mol) at ambient temperature was added Pd ₂ (PPh ₃ ) ₂ Cl ₂ (230mg, 0.328mmol) and triphenylphosphine (172mg, 0.656mmol). The solution was degassed by bubbling nitrogen into the solution for 20 minutes. Copper (I) iodide (125mg, 0.66mmol) and 3,3-diethoxyprop-1-yne (5.04g, 39.3mmol) were then added sequentially and the reaction was stirred under nitrogen for 18 h. The precipitate (triethylamine hydrochloride) was collected by filtration and washed with EtOAc (ca 20 mL). The filtrate was concentrated under reduced pressure and the residue was passed through SiO ₂ Upper chromatography [ Biotage KP-Sil 100g, eluted with 0% to 50% EtOAc in heptane]And (5) purifying. The product-containing fractions were combined and concentrated in vacuo to give the title compound as an orange oil (8.19 g, quantitative).

The method B comprises the following steps: LC-MS (electrospray): m/z =262.3 (M + H) ⁺ RT =1.65 min.

And 2, step: 2- (diethoxymethyl) -1H-indole-6-carbonitrile

To a stirred solution of 3-amino-4- (3,3-diethoxyprop-1-ynyl) benzonitrile (8.00g, 31.1mmol) in NMP (99 mL) at 0 deg.C was addedPotassium tert-butoxide (6.98g, 62.2mmol) was added (the solution changed from orange to dark red in color). After warming to room temperature, the solution was stirred at ambient temperature for 16 hours. Saturated aqueous ammonium chloride (25 mL) was added and the resulting mixture was partitioned between EtOAc (250 mL) and water (250 mL). The layers were separated and the organic layer was washed two more times with water (2X 200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a brown oil. The first aqueous layer was re-extracted with EtOAc (200 mL) and the layers were separated. The organic layer was washed twice with water (2X 200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil. Passing the crude material through SiO ₂ Upper chromatography [ BIOTAGE KP-Sil 100g, eluted with 0% to 50% EtOAc in heptane]And (5) purifying. The product containing fractions were combined and concentrated in vacuo. The residue (yellow solid) was recrystallized from EtOAc/heptane to give the title compound (5.86g, 24.0mmol, 77%) as a colorless crystalline solid.

The method B comprises the following steps: LC-MS (electrospray): m/z =262.3 (M + H) ⁺ RT =1.69 min.

And 3, step 3: [2- (diethoxymethyl) -1H-indol-6-yl ] methylamine

To a degassed solution of 2- (diethoxymethyl) -1H-indole-6-carbonitrile (5.8g, 24mmol) in ethanol (70 mL) was added ammonia in MeOH (7M, 20mL, 0.14mmol) and the reaction was degassed and backfilled with nitrogen 3 times. Raney nickel (Raney nickel) (assumed to be 50%, about 5.4g, 0.1mmol) was added and the reaction was evacuated and backfilled with nitrogen 3 times. The flask was evacuated last time and placed under a hydrogen atmosphere and stirred at ambient temperature for 3 hours. More raney nickel (ca 2.7 g) was added and the reaction was evacuated and placed under a hydrogen atmosphere and stirred at ambient temperature for 16 hours. The catalyst was removed by filtration (via Kieselguhr) and washed with methanol (50 mL). The filtrate was concentrated under reduced pressure to give the title compound (5.96g, 100%) as a colorless oil which crystallized upon standing.

The method C comprises the following steps: LC-MS (electrospray): m/z =247.3 (M-H) ^- RT =2.74 min.

And 4, step 4: n- [ (2-formyl-1H-indol-6-yl) methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

To a stirred solution of 4-oxopyrido [1,2-a ] pyrimidine-2-carboxylic acid (455mg, 2.39mmol) (intermediate 1) and DIPEA (1.0mL, 5.98mmol) in DMF (10 mL) was added HATU (910mg, 2.39mmol). The color was observed to change from colorless to green and form a suspension. After stirring at ambient temperature for an additional 30 minutes, a solution of [2- (diethoxymethyl) -1H-indol-6-yl ] methylamine (500mg, 1.99mmol) in DMF (5 mL) was added dropwise to the reaction. The color was observed to change from green to red and the reaction became homogeneous and was stirred at ambient temperature overnight.

The mixture was washed with EtOAc (100 mL) and saturated NaHCO ₃ The solutions (50 mL) were partitioned between. The organic layer was separated, washed with water (80 mL) and brine (20 mL), and dried (Na) ₂ SO ₄ ) Filtered and concentrated under reduced pressure to give a viscous red oil.

The crude product was dissolved in THF (10 mL), water (1 mL) and acetic acid (0.5 mL) were added and the mixture was stirred at ambient temperature for 2 hours.

THF was removed in vacuo and water (10 mL) was added to the resulting mixture, resulting in the precipitation of additional solid. The brown solid was collected by washing with water (2 × 5 mL) followed by diethyl ether (3 × 5 mL) and dried under vacuum to give the title compound as a brown solid (520mg, 75%).

The method C comprises the following steps: LC-MS (electrospray): m/z =347.2 (M + H) ⁺ RT =2.37 minutes.

And 5: n- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2-formyl-1H-indol-6-yl) methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide (185mg, 0.53mmol), DCE (5 mL), and 1-cyclobutylmethylamine (0.13mL, 1.0mmol) were charged into a pressure vial at ambient temperature. The vial was sealed and the mixture was stirred at 65 ℃ for 2 hours. After cooling to room temperature, sodium triacetoxyborohydride (340mg, 1.85mmol) was added and the mixture was heated to 65 ℃ for 2 hours.

The mixture was partitioned between EtOAc (40 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was separated, washed with brine (20 mL), and dried (Na) ₂ SO ₄ ) Filtered and concentrated under reduced pressure. The residue (pale yellow oil) was purified by reverse phase chromatography (basic method, SNAP ULTRA30g column, assay with MeCN +0.1 nh ₃ /H ₂ O+0.1％NH ₃ 10% to 90% elution). Fractions containing the desired product were freeze-dried overnight to give the title compound as an off-white solid (85mg, 38%).

The method C comprises the following steps: LC-MS (electrospray): m/z =416.4 (M + H) ⁺ RT =3.14 min.

Example 6: n- [ [2- [ [ (1-methylcyclopropyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

(1-methylcyclopropyl) methylamine hydrochloride (70mg, 0.577mmol) was added to N- [ (2-formyl-1H-indol-6-yl) methyl in a pressure vial]-4-oxo-pyrido [1,2-a]A solution of pyrimidine-2-carboxamide (100mg, 0.289mmol) in DCE (7 mL) and the RM stirred at 60 ℃ for 3 h. (1-methylcyclopropyl) methylamine hydrochloride (70mg, 0.577mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.30mL, 1.73mmol) were added and the reaction stirred at 60 ℃ for 1 h. The mixture was cooled to room temperature and added dropwise to NaBH over 5 minutes ₄ (111mg, 0.289mmol) in ethanol (2.5 mL). The mixture was stirred at ambient temperatureOvernight. NaBH added dropwise in ethanol (2.5 mL) ₄ (11mg, 0.289mmol) and the reaction stirred at ambient temperature for another 1 hour. The mixture was quenched with water (30 mL), extracted with DCM (3 × 40 mL), passed through a Telos phase separator and concentrated in vacuo. The residue was purified by preparative HPLC (method B) and the product-containing fractions were combined, concentrated in vacuo and lyophilized overnight to give the title compound as a pale yellow solid (70mg, 59%).

The method C comprises the following steps: LC-MS (electrospray): m/z =416.5 (M + H) ⁺ RT =3.16 min

The compounds in table 1 were prepared in the same manner as in examples 2 and 3 using commercial amines or the intermediates.

TABLE 1

Example 42: 4-oxo-N- [ [2- [ (2,2,2-trifluoroethylamino) methyl ] -1H-indol-6-yl ] methyl ] pyrido [1,2-a ] pyrimidine-2-carboxamide

2,2,2-trifluoroethylamine (25. Mu.L, 0.318 mmol) was added to N- [ (2-formyl-1H-indol-6-yl) methyl in a pressure vial]-4-oxo-pyrido [1,2-a]Pyrimidine-2-carboxamide example 2 a solution of step 4 (55mg, 0.159mmol) in DCE (4 mL) and 1,1,1,3,3,3-hexafluoro-2-propanol (2 mL) was prepared and the mixture was stirred at 50 ℃ for 1 hour. The mixture was cooled to room temperature and retreated with 2,2,2-trifluoroethylamine (25 μ L,0.318 mmol) and left to stir at 50 ℃ for 2.5 hours. The mixture was cooled to room temperature and added dropwise to NaBH over 5 minutes ₄ (18mg, 0.476mmol) in ethanol (2 mL). The mixture was stirred at ambient temperature overnight. The mixture is treated with NaBH ₄ (18mg, 0.476mmol) was retreated and left to stir at ambient temperature for 1 hour 15 minutes. The mixture was quenched with water (30 mL) and extracted with DCM (3X 40 mL). The combined organic layers were passed through an Isolute phase separator and concentrated in vacuo. The crude material was purified by preparative HPLC (method B) to give the title compound as an off-white solid (40.2mg, 59%).

The method C comprises the following steps: LC-MS (electrospray): m/z =430.3 (M + H) ⁺ RT =2.94 min

Example 70: n- [ [2- [ [ cyclobutylmethyl (methyl) amino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

To a solution of N- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide (200mg, 0.481 mmol) in chloroform (3 mL) and 2-propanol (1 mL) was added N-ethyl-N-isopropyl-propan-2-amine (0.25ml, 1.44mmol) and methyl iodide (30 μ L,0.481 mmol) at ambient temperature and the mixture was stirred for 4 hours. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (3 mL) and purified by preparative HPLC (method B). The product containing fractions were combined and concentrated to dryness under reduced pressure. The residue was dissolved in a 1:1 mixture of acetonitrile and water (4 mL) and lyophilized to give the title compound as a light yellow solid (65mg, 31%).

The method C comprises the following steps: LC-MS (electrospray): m/z =430.4 (M + H) ⁺ RT =3.62 min

Example 43: n- [ (2- { [ N- (cyclobutylmethyl) acetylamino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

To a solution of N- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide example 2 (150mg, 0.350mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.18ml, 1.05mmol) in DCM (5 mL) was added acetic anhydride (36 μ L,0.385 mmol) at ambient temperature and the mixture was stirred for 2 hours. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (method B) to give the title compound as a white solid (139mg, 85.9%).

The method E comprises the following steps: LC-MS (electrospray): m/z =458.2 (M + H) ⁺ RT =3.01 min

Example 44: 4-oxo-N- { [2- (piperidin-2-yl) -1H-indol-6-yl ] methyl } -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

Step 1:2- [2- (2-amino-4-cyano-phenyl) ethynyl ] piperidine-1-carboxylic acid tert-butyl ester

To a solution of 3-amino-4-iodobenzonitrile (1.05g, 4.30mmol) in anhydrous THF (5 mL) and triethylamine (10mL, 71.7mmol) were added bis (triphenylphosphine) palladium (II) chloride (30mg, 0.0430mmol) and triphenylphosphine (23mg, 0.0861mmol) at room temperature. The solution was degassed by bubbling nitrogen into the solution for 15 minutes. Copper (I) iodide (1695g, 0.0861mmol) and 2-ethynylpiperidine-1-carboxylic acid tert-butyl ester (0.99g, 4.73mmol) were then added sequentially and the reaction stirred under nitrogen for 4 hours. The precipitate (triethylamine hydroiodide) was collected by filtration and washed with EtOAc (ca 20 mL). The filtrate was concentrated under reduced pressure and the residue was passed through SiO ₂ Upper chromatography (elution with 0% to 50% etoac in heptane) purification. The fractions containing the product were combined and concentrated in vacuo. The orange solid was triturated with heptane. The resulting solid was collected by filtration, washed with heptane (about 25 mL) and dried in a vacuum oven at 45 ℃ for 2 hours to give the title compound as a white solid (1.03g, 70%).

The method C comprises the following steps: LC-MS (electrospray): m/z =651.5 (2M + H) ⁺ RT =4.21 min

Step 2:2- (6-cyano-1H-indol-2-yl) piperidine-1-carboxylic acid tert-butyl ester

To 2- [2- (2-amino-4-cyano-phenyl) ethynyl group at 0 DEG C]A stirred solution of tert-butyl piperidine-1-carboxylate (1.00g, 3.07mmol) in anhydrous NMP (12 mL) was added potassium 2-methylpropane-2-olate (0.69g, 6.15mmol) (the color of the solution changed from colorless to orange within seconds). Under nitrogenAfter warming to room temperature under an atmosphere for 16 hours. Ammonium chloride (saturated, 5 mL) was added and the resulting mixture was partitioned between EtOAc (100 mL) and water (80 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with water (2X 50 mL) and brine (30 mL) and dried (Na) ₂ SO ₄ ) Filtered and concentrated under reduced pressure. The residue (brown solid) was passed through SiO ₂ Upper chromatography (elution with 0% to 50% etoac in heptane) purification. The product containing fractions were combined and concentrated in vacuo. The residue (orange solid) was triturated with heptane. The resulting solid was collected by vacuum filtration, washed with heptane (10 mL) and dried in a vacuum oven at 45 ℃ for 2 hours to give the title compound as a white solid (875mg, 87%).

The method C comprises the following steps: LC-MS (electrospray): m/z =326.3 (M + H) ⁺ RT =4.19 min

And step 3:2- [6- (aminomethyl) -1H-indol-2-yl ] piperidine-1-carboxylic acid tert-butyl ester

The title compound (785mg, 83%) was prepared from tert-butyl 2- (6-cyano-1H-indol-2-yl) piperidine-1-carboxylate using the chemistry described in example 2, step 3.

The method E comprises the following steps: LC-MS (electrospray): m/z =330.2 (M + H) ⁺ RT =2.22 min.

And 4, step 4:2- {6- [ ({ 4-oxo-4H-pyrido [1,2-a ] pyrimidin-2-yl } carboxamido) methyl ] -1H-indol-2-yl } piperidine-1-carboxylic acid tert-butyl ester

To 4-oxopyrido [1,2-a]Pyrimidine-2-carboxylic acid (135mg, 0.711mmol) (intermediate 1), N-ethyl-N-isopropyl-propan-2-amine (0.11mL, 0.647mmol) and 2- [6- (aminomethyl) -1H-indol-2-yl]A solution of tert-butyl piperidine-1-carboxylate (213mg, 0.647mmol) in anhydrous DMF (4 mL) was added HATU (246mg, 0.647mmol) andthe mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between EtOAc (60 mL) and water (40 mL). The organic layer was separated, washed with water (40 mL) and brine (20 mL), and dried (Na) ₂ SO ₄ ) Filtered and concentrated to dryness in vacuo. Passing the residue through SiO ₂ Upper chromatography (elution with 0% to 100% etoac in heptane) purification. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a yellow oil (313mg, 92%).

The method C comprises the following steps: LC-MS (electrospray): m/z =502.4 (M + H) ⁺ RT =3.89 min

And 5: 4-oxo-N- { [2- (piperidin-2-yl) -1H-indol-6-yl ] methyl } -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

A solution of 2- {6- [ ({ 4-oxo-4H-pyrido [1,2-a ] pyrimidin-2-yl } carboxamido) methyl ] -1H-indol-2-yl } piperidine-1-carboxylic acid tert-butyl ester (96%, 313mg,0.599 mmol) in 4M HCl (4.5 mL) in dioxane was stirred at 40 ℃ for 2 hours [ the solution turned deep red and gas evolution ceased ]. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (3 mL) and passed through preparative HPLC (method B). The product containing fractions were combined and concentrated to dryness in vacuo. The residue was dissolved in acetonitrile (2 mL) and water (2 mL) and lyophilized to give the title compound as a pale yellow solid (120mg, 49%).

The method C comprises the following steps: LC-MS (electrospray): m/z =402.5 (M + H) ⁺ RT =2.77 minutes

Example 45: n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -3-fluoro-1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

Step 1: n- [ (3-fluoro-2-formyl-1H-indol-6-yl) methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

To N- [ (2-formyl-1H-indol-6-yl) methyl at room temperature]-4-oxo-pyrido [1,2-a]To a solution of pyrimidine-2-carboxamide (95%, 530mg, 1.45mmol) in anhydrous NMP (10 mL) was added 1-chloromethyl-4-fluoro-1,4-diazobicyclo [2.2.2]Octane bis (tetrafluoroborate) (515mg, 1.45mmol) and the mixture was stirred for 3 days. The mixture was diluted with EtOAc (100 mL), washed with water (50 mL) and brine (20 mL), and dried (Na) ₂ SO ₄ ) And concentrated under reduced pressure. The residue was purified by preparative HPLC (method B). The product-containing fractions were combined and concentrated to dryness to give the title compound as an off-white solid (97mg, 15%).

The method C comprises the following steps: LC-MS (electrospray): m/z =365.3 (M + H) ⁺ RT =2.60 min

Step 2: n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -3-fluoro-1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

The title compound (40mg, 43.5%) was prepared in the same manner as in step 5 of example 2.

The method C comprises the following steps: LC-MS (electrospray): m/z =434.4 (M + H) ⁺ RT =3.29 min

Example 46: n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1-methyl-1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

Step 1:2- (diethoxymethyl) -1-methyl-1H-indole-6-carbonitrile

To a slurry of sodium hydride (60%, 266mg, 6.65mmol) in DMF (1 mL) at 0 deg.C was added a solution of 2- (diethoxymethyl) -1H-indole-6-carbonitrile (650mg, 2.66mmol) in DMF (1 mL). The reaction was allowed to warm to room temperature for 10 minutes and then cooled back to 0 ℃. Methyl iodide (0.33mL, 5.32mmol) was added dropwise to the slurry and the reaction was stirred at 0 ℃ for 5 minutes and then allowed to warm to room temperature. The reaction was stirred for 1 hour. The mixture was cooled to 0 ℃ and quenched by dropwise addition of water (3 mL). The mixture was diluted with EtOAc (5 mL) and the layers were separated. The aqueous layer was extracted twice more with EtOAc (2X 5 mL). The organic layers were combined and washed with brine (5 mL), mgSO ₄ Dried, filtered and concentrated in vacuo to give the crude product as a yellow oil. Passing the crude material through SiO ₂ Up chromatography [0% to 50% EtOAc/heptane]Purification was performed to obtain the title compound (624mg, 90%) as a white solid.

The method B comprises the following steps: LC-MS (electrospray): m/z =259.1 (M + H) ⁺ RT =0.68 min

And 2, step: 1- [2- (diethoxymethyl) -1-methyl-1H-indol-6-yl ] methylamine

The title compound (570mg, 90%) was prepared in the same manner as in example 2, step 3.

The method B comprises the following steps: LC-MS (electrospray): m/z =263.3 (M + H) ⁺ RT =1.75 min

And 3, step 3: n- [ (2-formyl-1-methyl-indol-6-yl) methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

T3P (50%, 1.6mL, 2.61mmol) was added to 4-oxopyrido [1,2-a)]Pyrimidine-2-carboxylic acid (454mg, 2.39mmol) (MediumIntermediate 1), [2- (diethoxymethyl) -1-methyl-indol-6-yl]A solution of methylamine (570mg, 2.17mmol) and DIPEA (1.9mL, 10.9mmol) in DMF (10 mL) was added, and the mixture was stirred at ambient temperature overnight. The mixture was retreated with T3P (50%, 1.6mL, 2.61mmol) and DIPEA (1.9mL, 10.9mmol) and stirred at ambient temperature for 2 h. The mixture was washed with DCM and H ₂ O, layers were separated, the mixture was extracted with DCM (3X 10 mL), the organic layer was passed through a TELOS phase separator and concentrated. Passing the crude material through SiO ₂ Up chromatography [0% to 100% EtOAc/heptane]Purification to give the title compound as an off-white solid (369mg, 46%).

The method A comprises the following steps: LC-MS (electrospray): m/z =361.1 (M + H) ⁺ RT =1.06 min

And 4, step 4: n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1-methyl-1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

1-Cyclobutylmethylamine (87mg, 1.02mmol) was added to N- [ (2-formyl-1-methyl-indol-6-yl) methyl group ]-4-oxo-pyrido [1,2-a]A solution of pyrimidine-2-carboxamide (184mg, 0.511mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (18.437 mL) and the mixture was stirred at ambient temperature for 30 min. 1-cyclobutylmethylamine (87mg, 1.02mmol) was added and the mixture was stirred at ambient temperature for 1 hour, then the mixture was heated to 40 ℃ for 2 hours. Additional 1-cyclobutylmethylamine (87mg, 1.02mmol) was added and the mixture was stirred at ambient temperature overnight. Adding NaBH to the mixture ₄ (58mg, 1.53mmol), then a few drops of MeOH were added and stirred at ambient temperature for 30 min. The mixture was quenched with MeOH (10 mL) at 0 ℃ and concentrated in vacuo. The residue was taken up in saturated NaHCO ₃ (aq) (10 mL) was partitioned with DCM (10 mL) and the phases separated. The aqueous phase was extracted with DCM (2 × 10 mL) and the combined organic phases were passed through a TELOS phase separator and concentrated in vacuo. The residue was purified by preparative HPLC (method B) to give the title compound as a light yellow solid(119mg，54.3％)。

The method C comprises the following steps: LC-MS (electrospray): m/z =430.6 (M + H) ⁺ RT =3.42 min

Example 47: n- [ [2- [ (cyclobutylmethylamino) -dideutero-methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

Step 1: 6-cyano-1H-indole-2-carboxylic acid

To a suspension of methyl 6-cyano-1H-indole-2-carboxylate (1.00g, 5.00mmol) in MeOH (15 mL) at ambient temperature was added 1M sodium hydroxide (7.5ml, 7.49mmol). The mixture was stirred at 40 ℃ for 2 hours. After cooling to room temperature, the reaction was acidified with 2M HCl (5 mL) and water (20 mL) was added. The resulting precipitate was collected by vacuum filtration, washed with water (50 mL) and dried in a vacuum oven at 45 ℃ overnight to give the title compound as a pale yellow solid (926 mg, 95%).

The method A comprises the following steps: LC-MS (electrospray): m/z =185.2 (M-H) -, RT =0.98 min

Step 2: 6-cyano-N- (cyclobutylmethyl) -1H-indole-2-carboxamides

To a solution of 6-cyano-1H-indole-2-carboxylic acid (97%, 626mg, 3.26mmol) in DMF (5 mL) at ambient temperature was added di (imidazol-1-yl) methanone (529mg, 3.26mmol). The mixture was stirred (large amount of gas generation) at 70 ℃ for 1 hour. The mixture was cooled to room temperature and 1-cyclobutylmethyl amine (361mg, 4.24mmol) was added. The mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with EtOAc (10 mL) and the solid filtered. To the filtrate were added water (50 mL) and ether (50 mL) with stirring. The resulting precipitate was collected by vacuum filtration, washed with water (20 mL) and diethyl ether (20 mL), and dried in a vacuum oven at 45 ℃ overnight to give the title compound as an off-white solid (550mg, 63%).

The method A comprises the following steps: LC-MS (electrospray): m/z =253.9 (M + H) ⁺ RT =1.14 min

And step 3:6- (aminomethyl) -N- (cyclobutylmethyl) -1H-indole-2-carboxamide

The title compound (487mg, 94%) was prepared in the same manner as in step 3 of example 2.

The method C comprises the following steps: LC-MS (electrospray): m/z =258.1 (M + H) ⁺ RT =2.56 min

And 4, step 4:1- [6- (aminomethyl) -1H-indol-2-yl ] -N- (cyclobutylmethyl) -1,1-dideutero-methylamine

To tetrahydrogen (C) ² H ₄ ) To a cooled (ice bath) suspension of lithium aluminate (1-) (221mg, 5.83mmol) in anhydrous 1,4-dioxane (5 mL) was added 6- (aminomethyl) -N- (cyclobutylmethyl) -1H-indole-2-carboxamide (150mg, 0.583mmol) in one portion. The ice bath was removed and the mixture was stirred at reflux for 3 hours (heating block temperature 110 ℃). The mixture was cooled to 0 ℃ (ice bath) and quenched by dropwise addition of a mixture of THF (10 mL) and water (1 mL), followed by 2m naoh (0.2 mL). The mixture was stirred at ambient temperature for 30 minutes. The solids were removed by filtration (Kieselguhr) and washed with THF (20 mL). The filtrate was dried (Na) ₂ SO ₄ ) Filtered and concentrated to dryness under reduced pressure. The residue was dissolved in chloroform (2 mL) and heptane (10 mL) was added. The resulting precipitate was collected by vacuum filtration, washed with heptane (5 mL) and dried in a vacuum oven at 45 ℃ for 2 hours to give the title compound as a light yellow solid (114mg, 69%).

The method C comprises the following steps: LC-MS (electrospray): m/z =246.2 (M + H) ⁺ RT =2.96 min

And 5: n- [ [2- [ (cyclobutylmethylamino) -dideutero-methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

To 4-oxopyrido [1,2-a]Pyrimidine-2-carboxylic acid (78mg, 0.408mmol) (intermediate 1), 1- [6- (aminomethyl) -1H-indol-2-yl group]A solution of (E) -N- (cyclobutylmethyl) -1,1-dideutero-methylamine (86%, 116mg, 0.408mmol) and DIPEA (0.21mL, 1.22mmol) in DMF (3 mL) was added HATU (170mg, 0.448mmol). The reaction was stirred at ambient temperature overnight. The mixture was washed with EtOAc (600 mL) and saturated NaHCO ₃ The solutions (20 mL) were partitioned between. The organic layer was separated, washed with brine (10 mL), and dried (Na) ₂ SO ₄ ) Filtered and concentrated under reduced pressure. The residue was purified by open access preparative HPLC method a. The fractions containing the product were combined and concentrated in vacuo until most of the acetonitrile was removed (water bath temperature 45 ℃, pressure 100 mbar). The clear solution was basified with saturated aqueous sodium carbonate solution and extracted with 3:1 chloroform/2-propanol (3 × 40 mL). The combined extracts were washed with brine (40 mL) and dried (Na) ₂ SO ₄ ) Filtered and concentrated to dryness under reduced pressure. The residue was triturated with acetonitrile. The solid was collected by vacuum filtration, washed with acetonitrile (10 mL) and dried in a vacuum oven at 45 ℃ overnight to give the title compound as a white solid (63mg, 36%).

The method C comprises the following steps: LC-MS (electrospray): m/z =418.5 (M + H) ⁺ RT =3.14 min

Example 48: n- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -1H-indazole-4-carboxamide

Reacting N- [ (2-formyl-1H-indol-6-yl) methyl at ambient temperature]-1-tetrahydropyran-2-yl-indazole-4-carboxamide (150mg, 0.373mmol), DCE (4.3 mL) and 1-cyclobutylmethylamine (0.091mL, 0.745mmol) were charged into a pressure vial. The vial was sealed and the mixture was stirred at 65 ℃ for 2 hours. After cooling to room temperature, sodium triacetoxyborohydride (184mg, 0.866mmol) was added and the mixture was heated to 65 ℃ for 2 hours. The mixture was partitioned between EtOAc (40 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was separated, washed with brine (20 mL), and dried (Na) ₂ SO ₄ ) Filtered and concentrated under reduced pressure. Subjecting the orange residue to basic reverse phase chromatography (SNAP Ultra 30g column, meCN +0.1% ₃ /H ₂ O+0.1％NH ₃ 10% to 90%) of the crude product. The fractions containing pure product were concentrated in vacuo to give a beige residue. The crude material was redissolved in MeOH (1 mL) and DCM (4 mL) and 4M HCl in dioxane (1 mL) was added. The reaction was stirred at ambient temperature for 5 hours. The solvent was removed in vacuo and the crude pink solid was purified using a 2g-SCX column eluting first with MeOH (10 mL) and then with 2M ammonia in MeOH solution (10 mL). The second filtrate was concentrated in vacuo to afford the desired product as an off-white solid. The compound was lyophilized overnight to give the title compound as an off-white powder (78mg, 53%).

The method C comprises the following steps: LC-MS (electrospray): m/z =388.3 (M + H) ⁺ RT =2.96 min

Intermediate 2: n- (cyclobutylmethyl) -N-prop-2-ynyl-carbamic acid tert-butyl ester

To a solution of tert-butyl prop-2-yn-1-ylcarbamate (3.00g, 19.3 mmol) in anhydrous DMF (30 mL) at 0 deg.C was added sodium hydride (60%, 852mg,21.3 mmol). The mixture was stirred for 10 min, followed by the addition of (bromomethyl) cyclobutane (2.4ml, 21.3mmol). The resulting mixture was then stirred at ambient temperature overnight. The mixture was diluted with water (50 mL) and extracted with ether (3X 50 mL). Will be provided withThe combined organic extracts were washed with water (80 mL) and brine (30 mL), mgSO ₄ Dried, filtered and concentrated under reduced pressure. Passing the crude material through SiO ₂ Chromatography [ Sfar silica D column 50g; 0% to 20% EtOAc in heptane, 12CV]And (5) purifying. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colorless oil (3.12g, 13.3mmol, 69%).

Intermediate 3:6- (azidomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] pyrrolo [3,2-b ] pyridine-1-carboxylic acid tert-butyl ester

Step 1: 5-amino-6-bromo-pyridine-3-carboxylic acid methyl ester

NBS (6434mg, 36.1mmol) was added to a solution of methyl 5-aminopyridine-3-carboxylate (5000mg, 32.9mmol) in anhydrous DMF (50 mL), and the mixture was stirred at room temperature over the weekend. The mixture was diluted with water (250 mL) and extracted with EtOAc (250 mL). The combined organics were washed with water (250 mL) and brine (250 mL), dried over magnesium sulfate and evaporated to dryness. Passing the crude material through SiO ₂ Purification by chromatography (Biotage; 100g Sfar Duo; 0% to 100% EtOAc in heptane) was carried out to give the title compound as a yellow solid (2850mg, 25%).

The method A comprises the following steps: LC-MS (electrospray): m/z =231/233 (M + H) ⁺ RT =0.95 min

Step 2: 6-bromo-5- [ (2,2,2-trifluoroacetyl) amino ] pyridine-3-carboxylic acid methyl ester

TFAA (4.5ml, 32.2mmol) was added to a solution of methyl 5-amino-6-bromo-pyridine-3-carboxylate (70%, 3540mg,10.7 mmol) in DCM (30 mL) and the RM was stirred at ambient temperature for 3 hours. RM was evaporated to dryness to give methyl as an orange oil (5250mg, 99%).

The method A comprises the following steps: LC-MS (electrospray): m/z =327/329 (M + H) ⁺ RT =1.10 min

And 3, step 3:2- [ [ tert-Butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -1H-pyrrolo [3,2-b ] pyridine-6-carboxylic acid methyl ester

Reacting 6-bromo-5- [ (2,2,2-trifluoroacetyl) amino]A solution of pyridine-3-carboxylic acid methyl ester (66%, 5250mg,10.6 mmol) in anhydrous 1,4-dioxane (11 mL) was added to a suspension of N- (cyclobutylmethyl) -N-prop-2-ynyl-carbamic acid tert-butyl ester (95%, 2490mg,10.6 mmol) (intermediate 2), cuI (304mg, 1.59mmol), potassium phosphate (4562mg, 21.2mmol) and triphenylphosphine (834mg, 3.18mmol) in anhydrous 1,4-dioxane (55 mL). The resulting suspension was degassed with nitrogen for 10 minutes and then stirred at 110 ℃ for 2 hours. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between water (30 mL) and EtOAc (30 mL). The organic phases were collected and the aqueous phase was extracted with EtOAc (2X 30 mL). The combined organic phases were dried over magnesium sulfate and concentrated to give the crude material as a brown oil. Passing the crude material through SiO ₂ Purification by chromatography (Biotage Isolera Four;100g Sfar Duo; 10% to 60% EtOAc in heptane) followed by SiO ₂ Repurification on upper chromatography (Biotage Isolera Four;55g Sfar Amino D; 10% to 50% EtOAc in heptane) gave the title compound (1180 mg, 30%) as a white solid.

The method A comprises the following steps: LC-MS (electrospray): m/z =374.2 (M + H) ⁺ RT =1.07 min

And 4, step 4: 1-tert-butyl 6-methyl 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] pyrrolo [3,2-b ] pyridine-1,6-dicarboxylate

Boc anhydride (947mg, 4.34mmol) was added to 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino group]Methyl radical]-1H-pyrrolo [3,2-b]An ice-cold solution of pyridine-6-carboxylic acid methyl ester (1350mg, 3.61mmol) in DCM (28.602 mL) followed by DMAP (44mg, 0.361mmol). The mixture was warmed to room temperature and stirred for 30 minutes. Water (50 mL) was added and the mixture was extracted with DCM (3X 50 mL). The combined organics were dried over magnesium sulfate, evaporated to dryness and passed through SiO ₂ Purification by upper chromatography (55 g Sfar Amino D; 0% to 50% EtOAc in heptane) to give the title compound as a colorless oil (1630 mg, 95%).

The method B comprises the following steps: LC-MS (electrospray): m/z =474.3 (M + H) ⁺ RT =2.28 min

And 5:2- [ [ tert-Butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- (hydroxymethyl) pyrrolo [3,2-b ] pyridine-1-carboxylic acid tert-butyl ester

1M DIBAL (14mL, 13.5 mmol) in DCM was added to 1-tert-butyl 6-methyl 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino at-78 deg.C]Methyl radical]Pyrrolo [3,2-b]A solution of pyridine-1,6-dicarboxylate (1600mg, 3.38mmol) in anhydrous DCM (32 mL). The mixture was stirred at this temperature for 2 hours. The reaction was quenched with water (10 mL) at-78 ℃. The mixture was stirred for 10 minutes and then allowed to warm to room temperature. Water (50 mL) was added and the mixture was extracted with DCM (3X 50 mL). The combined organic phases are dried over magnesium sulfate, evaporated to dryness and passed over SiO ₂ Purification by chromatography (Biotage Isolera Four;55g Sfar Amino D; 0% to 100% EtOAc in heptane) gave the title compound (1160 mg, 74%) as a colorless oil.

The method A comprises the following steps: LC-MS (electrospray): m/z =446.3 (M + H) ⁺ RT =1.25 min

Step 6:6- (Azidomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] pyrrolo [3,2-b ] pyridine-1-carboxylic acid tert-butyl ester

DPPA (241. Mu.L, 1.12 mmol) was added to 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ]Methyl radical]-6- (hydroxymethyl) pyrrolo [3,2-b]An ice-cold solution of tert-butyl pyridine-1-carboxylate (250mg, 0.561mmol) and DBU (167. Mu.L, 1.12 mmol) in dry DMF (3.125 mL). The mixture was stirred at ambient temperature for 24 hours, an additional amount of DPPA (241 μ L,1.12 mmol) was added and the mixture was stirred at ambient temperature for 18 hours, then heated to 40 ℃ for 2 hours. The mixture was diluted with water (25 mL) and extracted with EtOAc (3X 20 mL). The combined organics were washed with brine (25 mL), dried over magnesium sulfate and evaporated to dryness. Passing the crude material through SiO ₂ Purification by upper chromatography (Biotage Isolera Four;28g Sfar Amino D; 0% to 100% EtOAc in heptane) to give the title compound as a colorless oil (140mg, 0.24, 44%).

The method A comprises the following steps: LC-MS (electrospray): m/z =471.3 (M + H) ⁺ RT =1.53 min

Example 49: n- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-pyrrolo [3,2-b ] pyridin-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

Step 1:6- (aminomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] pyrrolo [3,2-b ] pyridine-1-carboxylic acid tert-butyl ester

Triphenylphosphine (524mg, 2.00mmol) was added to an ice-cold solution of tert-butyl 6- (azidomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] pyrrolo [3,2-b ] pyridine-1-carboxylate (94%, 500mg, 0.999mmol) (intermediate 3) in THF (5 mL) and water (0.5 mL). The mixture was warmed to room temperature and stirred overnight. The mixture was evaporated to dryness and purified by basic reverse phase chromatography to give (55mg, 12%) as a colorless oil.

The method B comprises the following steps: LC-MS (electrospray): m/z =445.3 (M + H) ⁺ RT =1.89 min

And 2, step: 2- [ [ tert-Butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [ (4-oxopyrido [1,2-a ] pyrimidine-2-carbonyl) amino ] methyl ] pyrrolo [3,2-b ] pyridine-1-carboxylic acid tert-butyl ester

Reacting 6- (aminomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino group]Methyl radical]Pyrrolo [3,2-b]Pyridine-1-carboxylic acid tert-butyl ester (55mg, 0.124mmol), 4-oxopyrido [1,2-a]A mixture of pyrimidine-2-carboxylic acid (24mg, 0.124mmol) (intermediate 1), DIPEA (65. Mu.L, 0.371 mmol) and HATU (52mg, 0.136mmol) in DMF (1 mL) was stirred at ambient temperature over the weekend. The mixture was washed with saturated NaHCO ₃ Partitioned between aqueous (15 mL) and EtOAc (15 mL). The organic phase was collected, dried over magnesium sulphate and evaporated to dryness. Passing the crude material through SiO ₂ Purification by upper chromatography (11 g Sfar Amino D; 0% to 100% EtOAc in heptane) to yield the title compound as a yellow oil (51mg, 57%).

The method B comprises the following steps: LC-MS (electrospray): m/z =617.4 (M + H) ⁺ RT =1.91 min

And step 3: n- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-pyrrolo [3,2-b ] pyridin-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

4M HCl in dioxane (0.17mL, 0.697 mmol) was added to a solution of tert-butyl 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [ (4-oxopyrido [1,2-a ] pyrimidine-2-carbonyl) amino ] methyl ] pyrrolo [3,2-b ] pyridine-1-carboxylate (86%, 50mg, 0.0697mmol) in DCM (0.5 mL) and MeOH (0.5 mL). The mixture was stirred at 40 ℃ for 2 hours, then at room temperature overnight. The mixture was evaporated to dryness and purified by preparative HPLC (method B) to give the title compound as a white powder (15mg, 50%).

The method C comprises the following steps: LC-MS (electrospray): m/z =417.3 (M + H) ⁺ RT =2.32 min

Intermediate 12: n- [ [6- (aminomethyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] methyl ] -N- (cyclobutylmethyl) carbamic acid tert-butyl ester

Step 1: n- [3- (2-amino-6-chloro-3-pyridinyl) prop-2-ynyl ] -N- (cyclobutylmethyl) carbamic acid tert-butyl ester

To a solution of 6-chloro-3-iodopyridin-2-amine (0.96g, 3.77mmol) in anhydrous THF (5 mL) and triethylamine (9.0ml, 64.6 mmol) was added palladium chloride (2 +) -triphenylphosphine (1. The solution was degassed by bubbling nitrogen into the solution for 15 minutes. Copper iodide (1 +) (14mg, 0.0755mmol) and N- (cyclobutylmethyl) -N-prop-2-ynyl-tert-butyl carbamate (1.01g, 4.53mmol) were then added sequentially (intermediate 2) and the reaction was stirred under nitrogen for 4 hours. The precipitate (triethylamine hydroiodide) was collected by filtration and washed with EtOAc (ca 20 mL). The filtrate was concentrated under reduced pressure and the residue was passed through SiO ₂ Upper chromatography [ BIOTAGE Sfar Silica D-Duo 60 μm column, 0% to 50% EtOAc in heptane, 12CV]And (5) purifying. The product-containing fractions were combined and concentrated in vacuo to give the title compound as an orange oil which solidified on standing to give a brown solid (1.31g, 92%).

The method C comprises the following steps: LC-MS (electrospray): m/z =350.3 (M + H) ⁺ RT =4.54 min

And 2, step: n- [ (6-chloro-1H-pyrrolo [2,3-b ] pyridin-2-yl) methyl ] -N- (cyclobutylmethyl) carbamic acid tert-butyl ester

To N- [3- (2-amino-6-chloro-3-pyridyl) prop-2-ynyl at 0 DEG C]A stirred solution of tert-butyl (N- (cyclobutylmethyl) carbamate (93%, 1.41g, 3.74mmol) in anhydrous NMP (15 mL) was added potassium 2-methylpropane-2-olate (0.84g, 7.49mmol) (the solution changed color from orange to black within seconds). After warming to room temperature, the solution was stirred at ambient temperature under nitrogen atmosphere for 16 hours. Saturated aqueous ammonium chloride (5 mL) was added and the resulting mixture was partitioned between EtOAc (100 mL) and water (80 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with water (2X 50 mL) and brine (30 mL) and dried (Na) ₂ SO ₄ ) Filtered and concentrated under reduced pressure. Passing the residue through SiO ₂ Upper chromatography [ BIOTAGE Sfar Silica D-Duo 60 μm column 50g, 0% to 50% EtOAc in heptane, 12CV]And (5) purifying. The product containing fractions were combined and concentrated in vacuo. The residue (orange solid) was triturated with heptane. The resulting solid was collected by vacuum filtration, washed with heptane (10 mL) and dried in a vacuum oven at 45 ℃ for 2 hours to give the title compound as a white solid (650mg, 47%).

The method C comprises the following steps: LC-MS (electrospray): m/z =350.3/352.3 (M + H) ⁺ RT =4.60 min

And step 3: n- [ (6-cyano-1H-pyrrolo [2,3-b ] pyridin-2-yl) methyl ] -N- (cyclobutylmethyl) carbamic acid tert-butyl ester

N- [ (6-chloro-1H-pyrrolo [2,3-b) in a pressurized vial at ambient temperature]Pyridin-2-yl) methyl]Tert-butyl (N- (cyclobutylmethyl) carbamate (585mg, 1.67mmol) and zinc dicyanide (216mg, 1.84mmol) in the absence of waterDegassed suspension in NMP (7 mL) was supplemented with tBuXPhos Pd G3 (33mg, 0.0418mmol). The vial was sealed and the reaction was stirred at 120 ℃ for 2 hours. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (2X 50 mL). The combined organic extracts were washed with water (50 mL), saturated NaHCO ₃ (aqueous) solution (20 mL) and brine (20 mL) were washed with (Na) ₂ SO ₄ ) Dried, filtered and concentrated under reduced pressure. Passing the residue through SiO ₂ Chromatography [ BIOTAGE Sfar Silica D-Duo 60 μm column 25g, 0% to 100% EtOAc in heptane, 12CV]And (5) purifying. The product containing fractions (fraction 3) were concentrated in vacuo to give the title compound as a white solid (475mg, 79%).

The method C comprises the following steps: LC-MS (electrospray): m/z =341.4 (M + H) ⁺ RT =4.22 min

And 4, step 4: n- [ [6- (aminomethyl) -1H-pyrrolo [2,3-b ] pyridin-2-yl ] methyl ] -N- (cyclobutylmethyl) carbamic acid tert-butyl ester

To a degassed suspension of tert-butyl N- [ (6-cyano-1H-pyrrolo [2,3-b ] pyridin-2-yl) methyl ] -N- (cyclobutylmethyl) carbamate (475mg, 1.40mmol) in ethanol (20 mL) at ambient temperature was added 7M ammonia (5.0mL, 35.0mmol) and Raney nickel (164mg, 2.79mmol) in MeOH. The mixture was degassed again and stirred under hydrogen atmosphere for 16 hours. The catalyst was removed by filtration (celite) and washed with ethanol (about 20 mL). The filtrate was concentrated to dryness under reduced pressure to give the title compound (480 mg, 95) as a green oil.

The method C comprises the following steps: LC-MS (electrospray): m/z =345.4 (M + H) ⁺ RT =3.58 min

Example 71: n- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

Step 1: n- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

Using intermediate 12, the title compound (345mg, 64%) was prepared in the same manner as the precursor in example 42.

The method C comprises the following steps: LC-MS (electrospray): m/z =517.4 (M + H) ⁺ RT =3.92 min

Step 2: n- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

To a solution of tert-butyl N- (cyclobutylmethyl) -N- [ [6- [ [ (4-oxopyrido [1,2-a ] pyrimidine-2-carbonyl) amino ] methyl ] -1H-pyrrolo [2,3-b ] pyridin-2-yl ] methyl ] carbamate (90%, 730mg, 1.27mmol) in DCM (5 mL) was added TFA (5 mL) at ambient temperature. The mixture was stirred at ambient temperature until gas evolution ceased (about 1 hour). The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (6 mL) and purified by open access preparative HPLC method B. The product containing fractions were combined and concentrated to dryness in vacuo. The residue (colorless oil) was triturated with acetonitrile (5 mL). The resulting solid was collected by vacuum filtration, washed with acetonitrile (2 mL) and heptane (5 mL) and dried in a vacuum oven at 45 ℃ overnight to give the title compound as a white solid (345mg, 64%).

The method C comprises the following steps: LC-MS (electrospray): m/z =417.4 (M + H) ⁺ RT =2.85 min

Example 72: n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-1,3-benzoxadiazol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

Step 1: n- [ (5-cyano-1H-benzimidazol-2-yl) methyl ] carbamic acid tert-butyl ester

To a suspension of 3,4-diaminobenzonitrile (98%, 0.50g, 3.68mmol) and N- (tert-butoxycarbonyl) glycine (0.71g, 4.05mmol) in DCE (10 mL) at ambient temperature were added T3P (50%, 4.4mL, 7.36mmol) and N-ethyl-N-isopropyl-propan-2-amine (3.2mL, 18.4mmol) in EtOAc. The mixture was stirred in a pressure vial at 100 ℃ for 24 hours. After cooling to room temperature, the mixture was poured into saturated NaHCO ₃ Aqueous solution (25 mL). The organic layer was separated and the aqueous layer was extracted with DCE (2X 20 mL). The combined organic layers were washed with brine (20 mL) and dried (Na) ₂ SO ₄ ) Filtered and concentrated under reduced pressure. Passing the residue through SiO ₂ Chromatography [ SNAP Cartridge KP-Sil 25g; 0% to 100% EtOAc in heptane, 12CV]And (5) purifying. The product-containing fractions were combined and concentrated in vacuo to give an orange oil. Passing the product through SiO ₂ Upper chromatography [ SNAP Cartridge KP-Sil 25g; 0% to 100% EtOAc in DCM, 12CV ]And (5) purifying. The product containing fractions were combined and concentrated in vacuo. The residue was triturated with EtOAc/heptane to give the title compound as a gray solid (260mg, 25%).

The method C comprises the following steps: LC-MS (electrospray): m/z =273.1 (M-H) ^- RT =2.33 min

Step 2: n- [ [6- (aminomethyl) -1H-benzimidazol-2-yl ] methyl ] carbamic acid tert-butyl ester

The title compound (255mg, 95.5%) was prepared in the same manner as in example 2, step 3.

The method C comprises the following steps: LC-MS (electrospray): m/z =277.2 (M + H) ⁺ RT =1.85 min

And step 3: n- [ [6- [ [ (4-oxopyrido [1,2-a ] pyrimidine-2-carbonyl) amino ] methyl ] -1H-benzimidazol-2-yl ] methyl ] carbamic acid tert-butyl ester

To 4-oxopyrido [1,2-a]Pyrimidine-2-carboxylic acid (180mg, 0.945mmol) (intermediate 1), N- [ [6- (aminomethyl) -1H-benzimidazol-2-yl)]Methyl radical]A solution of tert-butyl carbamate (95%, 250mg,0.859 mmol) and DIPEA (0.45mL, 2.58mmol)) in DMF (7.5 mL) was added HATU (392mg, 1.03mmol). The reaction was stirred at ambient temperature overnight. The mixture was washed with EtOAc (80 mL) and saturated NaHCO ₃ The solutions (500 mL) were partitioned between. The organic layer was separated, washed with water (50 mL) and brine (20 mL), and dried (Na) ₂ SO ₄ ) Filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (method B) to give the title compound as a colorless solid (220mg, 55.9%).

The method C comprises the following steps: LC-MS (electrospray): m/z =449.3 (M + H) ⁺ RT =2.30 min

And 4, step 4: n- [ [2- (aminomethyl) -3H-benzimidazol-5-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide hydrochloride

To a solution of tert-butyl N- [ [6- [ [ (4-oxopyrido [1,2-a ] pyrimidine-2-carbonyl) amino ] methyl ] -1H-benzimidazol-2-yl ] methyl ] carbamate (202mg, 0.450mmol) in THF (3 mL) was added 4M hydrogen chloride (4.0 mL,16.0 mmol) in 1,4-dioxane, and the mixture was stirred at ambient temperature for 2 hours. Volatiles were removed under reduced pressure. The residue was dissolved in MeOH (3 mL) and diethyl ether (20 mL) was added. The resulting precipitate was collected by vacuum filtration, washed with diethyl ether (10 mL) and dried in a vacuum oven at 45 ℃ for 2 hours to give the title compound (165mg, 92%) as a white solid.

And 5: n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-1,3-benzoxadiazol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

Reacting N- [ [2- (aminomethyl) -3H-benzimidazol-5-yl ] at ambient temperature]Methyl radical]-4-oxo-pyrido [1,2-a]A solution of pyrimidine-2-carboxamide hydrochloride (100mg, 0.260mmol), N-ethyl-N-isopropyl-propan-2-amine (0.14mL, 0.780mmol) and cyclo Ding Jiaquan (95%, 23mg, 0.260mmol) in ethanol (5 mL) was stirred for 1 hour. The mixture was then cooled to 0 deg.C (ice bath) and sodium borate (10mg, 0.260mmol) was added. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was washed with ethyl acetate (40 mL) and 2M Na ₂ CO ₃ The aqueous solution (30 mL) was partitioned. The organic layer was separated, washed with brine (20 mL), and dried (Na) ₂ SO ₄ ) Filtered and concentrated under reduced pressure. The residue was purified by open access preparative HPLC method B. The product containing fractions were combined and concentrated to dryness. The residue was dissolved in a 1:1 (v/v) mixture of acetonitrile and water (4 mL). The resulting solution was lyophilized to give the title compound as a white solid (36mg, 33%).

The method C comprises the following steps: LC-MS (electrospray): m/z =417.3 (M + H) ⁺ RT =2.28 min

Example 50: n- (1H-indol-6-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

HATU (219mg, 0.575mmol) was added to a mixture of 4-oxopyrido [1,2-a ] pyrimidine-2-carboxylic acid (109mg, 0.575mmol) (intermediate 1) and DIPEA (0.24ml, 1.37mmol) in DMF (5.6 mL) and the mixture was stirred in DMF (5.6 mL). After 10 minutes 1H-indol-6-ylmethylamine (70mg, 0.479mmol) was added. And the reaction was stirred at ambient temperature overnight. Water (15 mL) was added to the reaction, and the mixture was extracted with DCM (15 mL). The organic phase was washed with brine (4 × 15 mL), dried, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (method B) to give the title compound as an off-white solid (30mg, 19%).

The method C comprises the following steps: LC-MS (electrospray): m/z =319.2 (M + H) ⁺ RT =2.55 min

Example 51: n- (1H-indol-2-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

The title compound was prepared in the same manner as in example 49 using DIPEA (0.36ml, 2.05mmol) as the amine (which is a salt).

The method C comprises the following steps: LC-MS (electrospray): m/z =319.2 (M + H) ⁺ RT =2.75 min

Example 52: n- (indolizin-2-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

The title compound was prepared in the same manner as in example 49.

The method C comprises the following steps: LC-MS (electrospray): m/z =319.2 (M + H) ⁺ RT =2.74 min

Intermediate 4: 7-ethynyl-1-tetrahydropyran-2-yl-indazoles

Step 1: 7-bromo-1-tetrahydropyran-2-yl-indazoles

1H-indazole 7-bromo (1g, 5.08mmol), tsOH, H ₂ O (193mg, 1.02mmol) and 3,4-dihydro-2H-pyran (923. Mu.L, 10.2 mmol) are combined in DCM (50 mL) and the mixture is stirred at ambient temperature overnight. The mixture was washed with saturated NaHCO ₃ (aq) (50 mL) quench and stir rapidly for 5 min. The phases were separated and the aqueous phase was extracted with DCM (2X 50 mL). The combined organic layers were passed over Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Purification was by chromatography on (50 g of Sfar Duo, eluting with EtOAc/heptane 0% to 100%) to give the title compound (543mg, 36%).

The method B comprises the following steps: LC-MS (electrospray): m/z =281.1/283.1 (M + H) ⁺ RT =1.77 minutes

Step 2: trimethyl- [2- (1-tetrahydropyran-2-ylindazol-7-yl) ethynyl ] silane

A mixture of 4-bromo-1-tetrahydropyran-2-yl-indazole (2.50g, 8.89mmol) and triethylamine (5.9mL, 42.5 mmol) in dry DMF (15 mL) was degassed for 5 minutes. Ethynyl (trimethyl) silane (3.7mL, 26.7mmol), cuI (170mg, 0.889mmol) and PdCl were added ₂ dppf (652mg, 0.889mmol), the mixture was degassed for a further 5 minutes, and then the mixture was stirred at 100 ℃ for 2 hours. The mixture was allowed to cool to room temperature and concentrated in vacuo to remove DMF. The material was dissolved in DCM (10 mL), passed through a plug of celite, washed with DCM (100 mL) and concentrated to give a crude brown solid. The crude material is dry-loaded onto silica and passed through SiO ₂ Purification by upper chromatography (50g, 0% to 30% EtOAc/heptane) to give the title compound as a brown oil (2.38g, 88%).

The method B comprises the following steps: LC-MS (electrospray): m/z =299.3 (M + H) ⁺ RT =2.15 min

And step 3: 7-ethynyl-1-tetrahydropyran-2-yl-indazoles

Dipotassium carbonate (2.20g, 15.9mmol) was added to trimethyl- [2- (1-tetrahydropyran-2-ylindazol-4-yl) ethynyl group ]A solution of silane (2.38g, 7.96mmol) in MeOH (15 mL) and the brown mixture was stirred at ambient temperature for 2 h (K) ₂ CO ₃ Not completely dissolved). The solvent was removed in vacuo. The residue was washed with DCM (20 mL) and H ₂ O (10 mL) dilution. The layers were separated and the aqueous layer was extracted with DCM (3X 15 mL). The combined organic extracts were washed with brine (20 mL), passed through a TELOS phase separator and concentrated in vacuo. The crude material was dry loaded onto a 30g KP-Sil column and passed through SiO ₂ Purification by upper chromatography (0% to 20% etoac/heptane) to give the title compound as a dark red solid (1.69g, 89%).

Method J: LC-MS (electrospray): m/z =227.1 (M + H) ⁺ RT =0.62 min

Intermediate 5: o1-tert-butyl O2-methyl 6- (azidomethyl) indole-1,2-dicarboxylate

Step 1: o1-tert-butyl O2-methyl 6-methylindole-1,2-dicarboxylate

Boc anhydride (13.84g, 63.4 mmol) was added to a mixture of methyl 6-methyl-1H-indole-2-carboxylate (10.00g, 52.9 mmol) and DMAP (1.00g, 8.19mmol) in acetonitrile (100 mL). The mixture was stirred at ambient temperature for 10 minutes, then at 45 ℃ overnight. The mixture was cooled to room temperature. The solvent was removed in vacuo to give an orange solid. Dissolve the solid in EtOAc (50 mL) and use H ₂ O (20 mL) wash. Is divided intoThe layers were separated and the aqueous layer was extracted with EtOAc (3X 30 mL). The combined organic phases were washed with brine (50 mL), mgSO ₄ Dried, filtered and concentrated in vacuo. Passing the crude material through SiO ₂ Purification by chromatography (100 gKP-Sil, eluting with EtOAc/heptane 0% to 50%) afforded the title compound as a pale orange solid (14.21g, 93%).

The method B comprises the following steps: LC-MS (electrospray): m/z =290.2 (M + H) ⁺ RT =2.01 min

Step 2: o1-tert-butyl O2-methyl 6- (bromomethyl) indole-1,2-dicarboxylate

O1-tert-butyl O2-methyl 6-methylindole-1,2-dicarboxylate (3.00g, 10.4 mmol) in DCE (150 mL) was charged to 250mL LRBF, 1-bromopyrrolidine-2,5-dione (1.75g, 9.85mmol) and 2,2' - (E) -diazene-1,2-diylbis (2-methylpropionitrile) (170mg, 1.04mmol) were added, and the mixture was stirred at 75 ℃ for 2 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. Passing the crude material through SiO ₂ Purification by chromatography on (100 g KP-Sil,0% to 10% EtOAc/heptane) to yield the title compound as an off-white solid (3.12g, 79%).

The method B comprises the following steps: LC-MS (electrospray): m/z =368.1/370.2 (M + H) ⁺ RT =1.99 min

And step 3: o1-tert-butyl O2-methyl 6- (azidomethyl) indole-1,2-dicarboxylate

O1-tert-butyl O2-methyl 6- (bromomethyl) indole-1,2-dicarboxylate (1.80g, 4.89mmol) was dissolved in DMF (8.0488 mL) followed by the addition of NaI (72mg, 0.477mmol) and NaN ₃ (794 mg, 12.2mmol) and the reaction stirred at ambient temperature for 2 hours. Subjecting the mixture to hydrogenation with H ₂ O (10 mL) was quenched and extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (2X 50 mL) and dried overMgSO ₄ Dried, filtered and concentrated in vacuo. Passing the crude material through SiO ₂ Purification by chromatography (0% to 40% etoac/heptane) to give the title compound as a yellow oil (1.37g, 78%).

The method B comprises the following steps: LC-MS (electrospray): m/z =331.2 (M + H) ⁺ RT =1.97 min

Example 53: n- [ (6- { [4- (1H-indazol-4-yl) -1H-1,2,3-triazol-1-yl ] methyl } -1H-indol-2-yl) methyl ] cyclopropylamine

Step 1: o1-tert-butyl O2-methyl 6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) triazol-1-yl ] methyl ] indole-1,2-dicarboxylate

Mixing sodium ascorbate (1.24g, 6.20mmol) and CuSO ₄ (41mg, 0.254mmol) was added to a mixture of 1-tert-butyl 2-methyl 6- (azidomethyl) indole-1,2-dicarboxylate (1.37g, 4.14mmol) (intermediate 5) and 4-ethynyl-1-tetrahydropyran-2-yl-indazole (1.03g, 4.55mmol) (intermediate 4) in DMF (25 mL) and water (10 mL) and the mixture was stirred at ambient temperature for 3.5 hours, an additional amount of CuSO was added ₄ (41mg, 0.254mmol) and the mixture stirred at ambient temperature overnight. The mixture was diluted with 3:1 chloroform/isopropanol (40 mL) and water (30 mL) and the phases separated. The aqueous phase was extracted with 3:1 chloroform/isopropanol (2 × 30 mL) and the combined organic layers were washed with water (40 mL), passed through a TELOS phase separator and evaporated under vacuum. Passing the crude material through SiO ₂ Purification by upper chromatography (0% to 50% etoac/heptane, 50g D) Sfar) to give the title compound as an off-white solid (1.80g, 71%).

The method B comprises the following steps: LC-MS (electrospray): m/z =557.3 (M + H) ⁺ RT =1.98 min

Step 2:2- (hydroxymethyl) -6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) triazol-1-yl ] methyl ] indole-1-carboxylic acid tert-butyl ester

1M DIBAL-H (1M in DCM) (6.5mL, 6.47mmol) was slowly added to O1-tert-butyl O2-methyl 6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) triazol-1-yl at-78 deg.C]Methyl radical]A solution of indole-1,2-dicarboxylate (1.80g, 3.24mmol) in anhydrous DCM (40 mL) was added and the mixture was stirred at-78 deg.C for 1 hour. The mixture was retreated with 1M DIBAL-H (1M in DCM) (3.2mL, 3.24mmol) and stirred at-78 deg.C for 1 hour, followed by-40 deg.C for 2 hours. Additional 1M DIBAL-H (1.6 mL, 1.62mmol) was added to the mixture and stirred at-40 ℃ for 1.5H. The mixture was slowly quenched with MeOH (5 mL) at-40 deg.C, stirred for 5 min, then H was added dropwise ₂ O (5 mL) and the mixture was stirred vigorously at ambient temperature for 10 minutes. 1M NaOH (aq) (5 mL) was added to help dissolve the mixture. The organic solvent was removed in vacuo. The mixture was washed with DCM (40 mL) and H ₂ O (20 mL), layers were separated, the mixture was extracted with DCM (3X 10 mL), the organic layer was washed with brine, passed through a TELOS phase separator and concentrated. Passing the crude material through SiO ₂ Purification by upper chromatography (0% to 70% etoac/heptane) to give the title compound as a white solid (1.30g, 74%).

The method B comprises the following steps: LC-MS (electrospray): m/z =529.3 (M + H) ⁺ RT =1.79 min

And 3, step 3: 2-formyl-6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) triazol-1-yl ] methyl ] indole-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 2- (hydroxymethyl) -6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) triazol-1-yl ] methyl ] indole-1-carboxylate (1.45g, 2.75mmol) and manganese dioxide (2.39g, 27.5 mmol) in DCE (80 mL) was stirred at reflux (90 ℃ C.) for 1 hour. The reaction was cooled to room temperature and filtered through a pad of celite to remove solids. The solid was washed with EtOAc (50 mL). The filtrate was collected and the solvent was removed in vacuo to give the title compound as a yellow foam (1.37g, 87%).

The method B comprises the following steps: LC-MS (electrospray): m/z =527.2 (M + H) ⁺ RT =1.93 minutes

And 4, step 4: n- [ (6- { [4- (1H-indazol-4-yl) -1H-1,2,3-triazol-1-yl ] methyl } -1H-indol-2-yl) methyl ] cyclopropylamine

Cyclopropylamine (53. Mu.L, 0.760 mmol) was added to 2-formyl-6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) triazol-1-yl]Methyl radical]A solution of tert-butyl indole-1-carboxylate (200mg, 0.380mmol) in DCE (0.72 mL) and the mixture was stirred at 60 ℃ for 1 hour. The mixture was cooled to room temperature and added dropwise to NaBH over 5 minutes ₄ (14mg, 0.380mmol) in ethanol (1.44 mL). RM was stirred at ambient temperature overnight. Adding additional amount of NaBH ₄ (14mg, 0.380mmol) was added to the mixture and stirred at ambient temperature for 2 hours. The mixture was quenched with water and extracted with DCM (3 × 20 mL), the organic phase was passed through a TELOS phase separator and concentrated in vacuo. The mixture was diluted with MeOH (1.4 mL) and then treated with HCl (4M in dioxane, 1.4 mL) and the mixture was stirred at ambient temperature for 6 hours. The mixture was stirred at room temperature overnight. The mixture was stirred at 45 ℃ for 30 minutes, then concentrated in vacuo. The crude material was purified by preparative HPLC (method B) and custom methods to give the title compound as a white solid (32mg, 22%).

The method C comprises the following steps: LC-MS (electrospray): m/z =384.3 (M + H) ⁺ RT =2.84 min

The compounds in table 2 were prepared in the same manner as in example 52 using a commercial amine or the intermediate.

TABLE 2

Example 58: n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine

2-formyl-6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) triazol-1-yl]Methyl radical]Tert-butyl indole-1-carboxylate (50mg, 0.10mmol) and 1-cyclobutylmethylamine (1699 mmol) were combined in 1,1,1,3,3,3-hexafluoro-2-propanol (2 mL), and the mixture was incubated at ambient temperature for 30 minutes. To NaBH ₄ (11mg, 0.28mmol) a few drops of MeOH were added and the mixture was incubated briefly at ambient temperature. The reaction was quenched with MeOH (20 mL) and evaporated in vacuo. The residue was taken up in saturated NaHCO ₃ (aq) (10 mL) was partitioned with DCM (10 mL) and the phases separated. The aqueous phase was extracted with DCM (2X 15 mL) and the combined organic layers were washed with Na ₂ SO ₄ Dried and evaporated under vacuum. The residue was redissolved in MeOH (5 mL) and treated with 4M HCl in dioxane (5 mL) and incubated overnight at ambient temperature. The mixture was evaporated in vacuo and the residue was purified by preparative HPLC (method B) to give the title compound as an off-white solid (13mg, 33%).

The method D comprises the following steps: LC-MS (electrospray): m/z =412.3 (M + H) ⁺ RT =4.12 min

Example 59: n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-b ] pyridin-2-yl ] methylamine

Step 1:2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- (1-tetrahydropyran-2-ylidazin-4-yl) triazol-1-yl ] methyl ] pyrrolo [3,2-b ] pyridine-1-carboxylic acid tert-butyl ester

The reaction mixture was quenched with 4-ethynyl-1-tetrahydropyran-2-yl-indazole (19mg, 0.0850mmol) (intermediate 4), 6- (azidomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino [ ] -methyl- ] -indazole]Methyl radical]Pyrrolo [3,2-b]A mixture of tert-butyl pyridine-1-carboxylate (40mg, 0.0850mmol) (intermediate 3), copper sulphate (2.7mg, 0.0170mmol) and sodium ascorbate (19mg, 0.0935mmol) in DMF (1 mL) and water (0.2 mL) was stirred at ambient temperature overnight. The mixture was diluted with water and 10% meoh in DCM. The organic phase is collected using a Telos phase separator, evaporated to dryness under reduced pressure and passed over SiO ₂ Purification by upper chromatography (KP-NH; 0% to 100% EtOAc in heptane, followed by 0% to 20% MeOH in EtOAc) to afford the title compound as a colorless oil (26mg, 44%).

The method A comprises the following steps: LC-MS (electrospray): m/z =697.5 (M + H) ⁺ RT =1.81 min

Step 2: n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-b ] pyridin-2-yl ] methylamine

4M HCl in dioxane (0.19mL, 0.746mmol) was added to a solution of tert-butyl 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) triazol-1-yl ] methyl ] pyrrolo [3,2-b ] pyridine-1-carboxylate (26mg, 0.0373mmol) in MeOH (1 mL) and the mixture was stirred at room temperature over the weekend. The mixture was evaporated to dryness, purified by preparative HPLC (method B) and lyophilized to give the title compound as a white powder (7.0 mg, 45%).

The method D comprises the following steps: LC-MS (electrospray): m/z =413.4 (M + H) ⁺ RT =2.45 min

Intermediate 6: n- [ [6- (azidomethyl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methyl ] -N- (cyclobutylmethyl) carbamic acid tert-butyl ester

Step 1: 4-amino-5-bromo-pyridine-2-carboxylic acid methyl ester

NBS (2.29g, 12.9 mmol) was added to a solution of methyl 4-aminopyridine-2-carboxylate (98%, 2.00g,12.9 mmol) in DCE (60 mL), and the mixture was stirred at room temperature overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (3X 50 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulfate and evaporated to dryness to give the title compound as an off-white solid (2.47g, 79%).

The method B comprises the following steps: LC-MS (electrospray): m/z =231.1/233.1 (M + H) ⁺ RT =1.16 min

Step 2: 5-bromo-4- [ (2,2,2-trifluoroacetyl) amino ] pyridine-2-carboxylic acid methyl ester

TFAA (4.5ml, 32.0 mmol) was added to a solution of 4-amino-5-bromo-pyridine-2-carboxylic acid methyl ester (2.47g, 10.7 mmol) in DCM (30 mL) and the mixture was stirred at ambient temperature overnight. Initially, the white turbid mixture was completely dissolved and colorless by the morning. The mixture was evaporated to dryness to give the product as a TFA salt (4.7g, 97%). 55mg of the salt was taken, washed with DCM (2 mL) and saturated NaHCO ₃ Aqueous solution (2 mL) was diluted, layers were separated, the aqueous layer was extracted with DCM (3 × 2 mL), the organic layer was passed through a TELOS phase separator and concentrated to give 32mg of the title compound as a white solid (32mg, 0.85%).

The method B comprises the following steps: LC-MS (electrospray): m is/z＝327.0/329.0(M+H) ⁺ RT =0.90 min

And step 3:2- [ [ tert-Butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -1H-pyrrolo [3,2-c ] pyridine-6-carboxylic acid methyl ester

Reacting 5-bromo-4- [ (2,2,2-trifluoroacetyl) amino]A mixture of pyridine-2-carboxylic acid methyl ester (1.63g, 4.99mmol), N- (cyclobutylmethyl) -N-prop-2-ynyl-carbamic acid tert-butyl ester (1.34g, 5.99mmol) (intermediate 2) and 1,1,3,3-tetramethylguanidine (1.9mL, 15.0mmol) in anhydrous DMF (27.668 mL) was degassed for 5 minutes, copper iodide (iodocopper) (96mg, 0.499mmol) and palladium dichloride triphenylphosphine (422mg, 0.599mmol) were added and the mixture degassed for an additional 5 minutes, followed by stirring at 65 ℃ overnight. The mixture was retreated with palladium dichloride triphenylphosphine (422mg, 0.599 mmol) and copper iodide (96mg, 0.499 mmol), the mixture was degassed for 10 min, and then the mixture was stirred at 65 ℃ for another 2 h. The mixture was cooled to room temperature, filtered through celite and washed with EtOAc (300 mL). The mixture was concentrated and passed through SiO ₂ Purification by chromatography on (Sfar amino D Duo 55g,0% to 100% EtOAc/heptane) to give an impure material with substantial amounts of triphenylphosphine oxide as by-product. The material was loaded onto a 5g SCX column, passed through MeOH, then through 2.5M NH in MeOH solution ₃ . The latter fractions were collected and concentrated to give the title compound as a brown oil (784mg, 21%).

And 4, step 4: n- (cyclobutylmethyl) -N- [ [6- (hydroxymethyl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methyl ] carbamic acid tert-butyl ester

1M DIBAL-H (1M in DCM) (2.2mL, 2.25mmol) was slowly added to 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] at-78 deg.C]Methyl radical]-1H-pyrrolo [3,2-c]Pyridine-6-carboxylic acid methyl ester (50%, 839mg, 1.12mmol) in anhydrous DCM (13.879 mL)And the mixture was stirred at-78 ℃ for 2 hours. The mixture was warmed to-40 ℃, retreated with 1M DIBAL-H (1M in DCM) (1.1mL, 1.12mmol) and stirred at-40 ℃ for 3.5H. The mixture was slowly quenched with MeOH (5 mL) at-40 deg.C, stirred for 5 min, then H was added dropwise ₂ O (5 mL) and the mixture was stirred vigorously at ambient temperature for 10 minutes. 1M NaOH (aq) (5 mL) was added to help dissolve the mixture. The organic solvent was removed in vacuo. The mixture was washed with DCM (40 mL) and H ₂ O (20 mL) diluted, the layers were separated, the mixture was extracted with DCM (3 × 10 mL), the organic layer was washed with brine, passed through a TELOS phase separator and concentrated in vacuo.

Passing the crude product through SiO ₂ Purify by chromatography (0% to 70% etoac/heptane) to give the title compound as a light brown solid (128mg, 31%).

The method B comprises the following steps: LC-MS (electrospray): m/z =346.3 (M + H) ⁺ RT =1.61 min

And 5: n- [ [6- (azidomethyl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methyl ] -N- (cyclobutylmethyl) carbamic acid tert-butyl ester

Diphenylphosphororazidate (0.16mL, 0.741mmol) was added to N- (cyclobutylmethyl) -N- [ [6- (hydroxymethyl) -1H-pyrrolo [3,2-c)]Pyridin-2-yl]Methyl radical]An ice-cold solution of tert-butyl carbamate (128mg, 0.371mmol) and DBU (0.11mL, 0.741mmol) in anhydrous DMF (1.9347 mL). The mixture was stirred at ambient temperature for 6 hours. The mixture was stirred at 40 ℃ for 2 hours, then at ambient temperature overnight. The mixture was retreated with diphenyl phosphoramidate (0.16mL, 0.741mmol) and DBU (0.11mL, 0.741mmol) and stirred at 40 ℃ for 2 hours, followed by overnight at ambient temperature. The mixture was diluted with water (25 mL) and extracted with EtOAc (3X 20 mL). The combined organics were washed with brine (25 mL), dried over magnesium sulfate and evaporated to dryness. Passing the crude material through SiO ₂ Purification by chromatography on (11 g Sfar Amino D; 0% to 100% EtOAc in heptane),to give the title compound as a light brown solid (36mg, 24%).

The method B comprises the following steps: LC-MS (electrospray): m/z =371.3 (M + H) ⁺ RT =1.83 min

Example 60: n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methylamine

Step 1: n- (cyclobutylmethyl) -N- [ [6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methyl ] carbamic acid tert-butyl ester

4-ethynyl-1-tetrahydropyran-2-yl indazole (26mg, 0.117mmol), N- [ [6- (azidomethyl) -1H-pyrrolo [3,2-c]Pyridin-2-yl]Methyl radical]A mixture of tert-butyl (N- (cyclobutylmethyl) carbamate (36mg, 0.0972mmol) (intermediate 6), copper sulfate (3.1mg, 0.0194mmol) and sodium ascorbate (21mg, 0.107mmol) in DMF (1.1432 mL) and water (0.2286 mL) was stirred at ambient temperature for 2 hours. The mixture was washed with water and CHCl ₃ IPA 3:1 mixture dilution. And (5) separating the layers. The aqueous layer was washed with CHCl ₃ IPA (3X 40 mL). The organic phase was collected using a Telos phase separator and evaporated to dryness under reduced pressure. The material was purified by SCX (1 g), loaded with MeOH, washed with MeOH, followed by 2.5M NH ₃ MeOH solution eluted, and the following fractions were collected and concentrated to give the title compound as a light brown solid (67mg, 100%).

The method B comprises the following steps: LC-MS (electrospray): m/z =597.4 (M + H) ⁺ RT =1.96 min

And 2, step: n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methylamine

A solution of tert-butyl N- (cyclobutylmethyl) -N- [ [6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methyl ] carbamate (86%, 67mg, 0.0966mmol) in MeOH (0.5 mL) was treated with 4M HCl in dioxane (2 mL) and the mixture was stirred at ambient temperature overnight. The solvent was removed in vacuo. The crude material was purified by preparative HPLC (method B) and lyophilized to give the title compound as a white solid (8.0 mg, 19%).

The method C comprises the following steps: LC-MS (electrospray): m/z =413.4 (M + H) ⁺ RT =2.66 min

Intermediate 7:6- (azidomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] indole-1-carboxylic acid tert-butyl ester

Step 1: 4-iodo-3- [ (2,2,2-trifluoroacetyl) amino ] benzoic acid methyl ester

A stirred suspension of methyl 3-amino-4-iodobenzoate (5.19g, 18.7mmol) in DCM (51.9 mL) was treated with (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (7.8mL, 56.0mmol). The resulting solution was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to give an off-white solid, which was redissolved in DCM (40 mL) and passed through a silica plug in a plastic sintered tube. The silica was washed with DCM (450 mL) and the filtrate (about 500 mL) was concentrated in vacuo and dried in a vacuum oven at 45 ℃ for additional hours to give the title compound as an off-white solid (6.94g, 98%).

The method A comprises the following steps: LC-MS (electrospray): m/z =371.9 (M + H) ⁺ RT =1.18 min

And 2, step: 2- [ [ tert-Butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -1H-indole-6-carboxylic acid methyl ester

An oven dried three necked 100mL RBF equipped with a reflux condenser was flushed with nitrogen and charged with triphenylphosphine (0.68g, 2.61mmol), copper (I) iodide (0.25g, 1.30mmol), tripotassium phosphate (3.74g, 17.4 mmol), 4-iodo-3- [ (2,2,2-trifluoroacetyl) amino]Methyl benzoate (98%, 3.31g, 8.69mmol) and anhydrous 1,4-dioxane (40 mL). A solution of N- (cyclobutylmethyl) -N-prop-2-ynyl-carbamic acid tert-butyl ester (97%, 2.00g, 8.69mmol) (intermediate 2) in anhydrous 1,4-dioxane (8 mL) was added and the resulting viscous suspension was deoxygenated by passing a stream of nitrogen over 5 minutes. The mixture was placed in a preheated heating block at 110 ℃ and stirred rapidly at this temperature for 7.5 hours. The reaction was allowed to stand at ambient temperature overnight. The following day the mixture was heated to 110 ℃ for another 3 hours. The mixture was cooled and concentrated. The resulting brown paste was partitioned between water (60 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (3X 30 mL). The combined organic phases were washed with brine (40 mL). The combined aqueous phases were back-extracted with EtOAc (20 mL). All organics were combined, dried over magnesium sulfate and concentrated to give the crude product as a brown solid. By SiO ₂ Purification was performed by upper chromatography (0% to 70% EtOAc/heptane) (Kp-Sil 50g column) eluting in a gradient of EtOAc/heptane (0% to 100%). The product-containing fractions were combined to give the title compound as a brown solid (2.29g, 71%).

The method D comprises the following steps: LC-MS (electrospray): m/z =373.3 (M + H) ⁺ RT =5.46 min

And step 3: 1-tert-butyl 6-methyl 2- ({ [ (tert-butoxy) carbonyl ] (cyclobutylmethyl) amino } methyl) -1H-indole-1,6-dicarboxylate

Preparation of 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] contained in DCM (30 mL) in 250mL RBF]Methyl radical]-1H-indole-6-carboxylic acid methyl ester (2.29g, 6.15mmol). The flask was cooled in an ice bath and a solution comprising di-tert-butyl dicarbonate (1.61g, 7.38mmol) in DCM (20 mL) was added followed by N, N-dimethylpyridin-4-amine (75mg, 0.615mmol). The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was washed with water (40 mL). The aqueous phase was separated and extracted with DCM (2X 20 mL). The combined organic phases were washed with brine (20 mL), dried over magnesium sulfate and concentrated to give the crude product as a brown gum. By SiO ₂ Purification was performed by upper chromatography (KP-Sil 50g column) eluting in a gradient of EtOAc/heptane (0% to 50%). The product-containing fractions were combined to give the title compound as a pale yellow oil (2.54g, 86%).

The method B comprises the following steps: LC-MS (electrospray): m/z =473.3 (M + H) ⁺ RT =2.44 min

And 4, step 4:2- [ [ tert-Butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- (hydroxymethyl) indole-1-carboxylic acid tert-butyl ester

50mL of oven dried RBF was charged with 1-tert-butyl 6-methyl 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino group]Methyl radical]Indole-1,6-dicarboxylate (2.54g, 5.37mmol), purged with nitrogen and then added anhydrous DCM (20 mL). The solution was kept under nitrogen and cooled using a dry ice/acetone cooling bath. 1M diisobutylaluminum (6 mL,6 mmol) in DCM was added slowly with stirring of the substrate solution, and the addition of the reagent solution was carried out so as to allow the solution to flow down one side of the reaction flask for precooling. The mixture was stirred at dry ice/acetone bath temperature for 1 hour 20 minutes. 1M diisobutylaluminum (7.5mL, 7.5mmol) in DCM was added in a similar manner to that previously. The reaction was stirred at the cooling bath temperature for 1 hour 40 minutes. 1M diisobutylaluminum (7mL, 7mmol) in DCM was added. The mixture was stirred at the cooling bath temperature for 1 hour 45 minutes. At the temperature of the cooling bath, the reactants are mixedQuench with water (2 mL). After the gas evolution subsided, water (4 mL) was added and the reaction was allowed to warm to room temperature. The resulting emulsion was diluted with brine (50 mL) and extracted with DCM (3X 50 mL). The remaining aqueous phase was diluted with a saturated Rochelle salt (Rochelle salt) solution (50 mL) (improved phase separation) and extracted with DCM (50 mL). After standing overnight, the solution was extracted again with DCM (50 mL), diluted with 1M NaOH solution (50 mL) and extracted with DCM (50 mL). The combined organics were dried over magnesium sulfate and concentrated to give the crude product as a foam. By SiO ₂ Purification was performed by upper chromatography (50 g Kp-Sil column) eluting in a gradient of EtOAc/heptane (0% to 100%). The product-containing fractions were combined to give the title compound as a yellow oil (1.99g, 83%).

The method D comprises the following steps: LC-MS (electrospray): m/z =445.3 (M + H) ⁺ RT =5.67 min

And 5:6- (Azidomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] indole-1-carboxylic acid tert-butyl ester

Oven dried 10mL RBF was charged with 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino group]Methyl radical]Tert-butyl-6- (hydroxymethyl) indole-1-carboxylate (100%, 400mg, 0.900mmol) and anhydrous DMF (5 mL). DBU (269. Mu.L, 1.80 mmol) was added and the resulting solution was cooled in an ice bath and stirred. Diphenyl phosphoramidate (388. Mu.L, 1.80 mmol) was added and the mixture stirred, allowing to warm to room temperature for 24 hours. The mixture was diluted with water (5 mL) and extracted with DCM (2X 10 mL). The aqueous phase was diluted with brine (20 mL) and extracted with DCM (2X 10 mL). The organics were combined, washed with brine (5 mL), dried over magnesium sulfate and concentrated to give the crude product as a brown oil. By SiO ₂ Purification was performed by upper chromatography (Sfar duo silica 25g column) eluting in a gradient of EtOAc/heptane 0% to 100%. The product-containing fractions were combined to give the title compound (377mg, 83%) as a pale yellow oil.

The method C comprises the following steps: LC-MS (electrospray))：m/z＝470.4(M+H) ⁺ RT =5.44 min

Example 61: n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methylamine

Step 1:2- [ [ tert-Butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- (1-tetrahydropyran-2-ylidazol-7-yl) triazol-1-yl ] methyl ] indole-1-carboxylic acid tert-butyl ester

7-ethynyl-1-tetrahydropyran-2-yl-indazole (70mg, 0.31mmol) (intermediate 4), 6- (azidomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino]Methyl radical]Indole-1-carboxylic acid tert-butyl ester (145mg, 0.31mmol) (intermediate 7) and sodium ascorbate (74mg, 0.37mmol) were combined in DMF (4 mL) and water (1 mL) and CuSO was added ₄ (5mg, 0.03mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with EtOAc (40 mL) and washed with water (30 mL) and brine (5X 30 mL). Subjecting the organic layer to Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Purification by upper chromatography (10 g of Sfar Duo, eluting with EtOAc/heptane 0% to 100%) gave the title compound as a light yellow solid (127mg, 59%).

The method B comprises the following steps: LC-MS (electrospray): m/z =696.5 (M + H) ⁺ RT =2.41 min

Step 2: n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methylamine

Tert-butyl 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- (1-tetrahydropyran-2-ylidazol-7-yl) triazol-1-yl ] methyl ] indole-1-carboxylate (127mg, 0.18mmol) was dissolved in MeOH (5 mL) and treated with 4M HCl in dioxane (2 mL). The mixture was incubated at ambient temperature for 5 hours. The mixture was cooled to room temperature and evaporated under vacuum. The residue was purified by preparative HPLC (method B) and the product-containing fractions were combined and evaporated in vacuo to give the title compound as a white solid (30mg, 40%).

The method D comprises the following steps: LC-MS (electrospray): m/z =412.3 (M + H) ⁺ RT =4.56 min

Example 62:2- [1- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] triazol-4-yl ] pyrido [1,2-a ] pyrimidin-4-one

Step 1: 2-ethynylpyrido [1,2-a ] pyrimidin-4-one

2-Chloropyridino [1,2-a in a 20mL pressure vial]Pyrimidin-4-one (700mg, 3.88mmol), cuI (74mg, 0.388mmol), pdCl2dppf (284mg, 0.388mmol) and triethylamine (2.6 mL,18.5 mmol) were combined in dry DMF (4 mL) and the mixture was bubbled with nitrogen for 10 min. Ethynyl (trimethyl) silane (1.6 ml,11.6 mmol) was added and the mixture bubbled with nitrogen for an additional 5 minutes. The mixture was heated at 100 ℃ overnight. The mixture was cooled to room temperature and saturated NaHCO was used ₃ (aqueous solution) (50 mL). The mixture was extracted with DCM (3X 50 mL) and the combined organic extracts were extracted with saturated NaHCO ₃ (aqueous) (100 mL) over Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Upper chromatography (KP-NH, eluted in 0% to 50% etoac/heptane). Passing the crude material through SiO ₂ Purification by chromatography on (KP-NH, eluting in 0% to 50% EtOAc/heptane) to give the title compound as a brown solid (302 mg)，46％)。

The method B comprises the following steps: LC-MS (electrospray): m/z =171.2 (M + H) ⁺ RT =1.14 min

Step 2: 2-formyl-6- [ [4- (4-oxopyrido [1,2-a ] pyrimidin-2-yl) triazol-1-yl ] methyl ] indole-1-carboxylic acid tert-butyl ester

The title compound (181mg, 72%) was prepared in the same manner as tert-butyl 2-formyl-6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) triazol-1-yl ] methyl ] indole-1-carboxylate in example 52.

The method B comprises the following steps: LC-MS (electrospray): m/z =471.3 (M + H) ⁺ RT =1.65 min

And 3, step 3:2- [1- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] triazol-4-yl ] pyrido [1,2-a ] pyrimidin-4-one

1-cyclobutylmethylamine (0.073mL, 0.762mmol) was added to 2-formyl-6- [ [4- (4-oxopyrido [1,2-a ]]Pyrimidin-2-yl) triazol-1-yl ]Methyl radical]A solution of tert-butyl indole-1-carboxylate (179 mg, 0.381mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (8 mL) and the mixture was stirred at room temperature for 30 min. Addition of NaBH ₄ (43mg, 1.14mmol) followed by the addition of a few drops of MeOH. The mixture was stirred at ambient temperature for 1.5 hours. The mixture was quenched (slightly effervescent) with MeOH (10 mL) at 0 ℃ and concentrated in vacuo. The residue was washed with saturated NaHCO ₃ (aq) (20 mL) was partitioned between DCM (20 mL) and the phases separated. The aqueous phase was extracted with DCM (3X 20 mL) and the combined organic phases were taken over Na ₂ SO ₄ Dried, filtered and concentrated. The crude material was diluted with 4M HCl in dioxane (7 mL) and MeOH (0.5 mL) and the mixture was stirred at ambient temperature for 2 hours. The mixture was retreated with 4M HCl (5 mL) and MeOH (1 mL) in dioxane, and the mixture was stirred at ambient temperatureOvernight. The mixture was reprocessed with 4M HCl (3 mL) and MeOH (1 mL) in dioxane, and the mixture was stirred at ambient temperature for 2 hours. The solvent was removed from the mixture in vacuo. The residue was purified by preparative HPLC (method B) and fractions containing pure product were combined, concentrated in vacuo and lyophilized overnight to give the title compound as a white solid (79mg, 47%).

The method C comprises the following steps: LC-MS (electrospray): m/z =440.4 (M + H) ⁺ RT =3.15 min

Example 63: n- (cyclobutylmethyl) -1- [6- [ [4- (6-methoxyimidazo [1,5-a ] pyridin-8-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine

Step 1: 3-bromo-5-methoxy-pyridine-2-carbonitrile

Sodium methoxide (296mg, 5.47mmol) was added to an ice-cold solution of 3-bromo-5-fluoropyridine-2-carbonitrile (1000mg, 4.98mmol) in MeOH (15 mL). The RM was warmed to room temperature and stirred for 1.5 hours. Sodium methoxide (296 mg, 5.47mmol) was added and the RM stirred at ambient temperature for 1 hour, heated to 40 ℃ for 4 hours, then allowed to stand at ambient temperature over the weekend. Sodium methoxide (150 mg) was added to the solution, and the mixture was stirred at 60 ℃ for 4 hours. The mixture was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Passing the residue through SiO ₂ Purification by upper chromatography (25 g SNAP Duo; 0% to 100% EtOAc in heptane) to yield the title compound as a white powder (1130mg, 106%).

The method A comprises the following steps: LC-MS (electrospray): m/z =213/215 (M + H) ⁺ RT =1.05 min

Step 2: (3-bromo-5-methoxy-2-pyridyl) methylamine

1M DIBAL in DCM (16mL, 15.9mmol) was added to an ice-cold solution of 3-bromo-5-methoxy-pyridine-2-carbonitrile (1130mg, 5.30mmol) in DCE (11 mL). The mixture was warmed to room temperature and stirred for 16 hours. The mixture was cooled to 0 ℃ with saturated NH ₄ Quenched with Cl (aq), basified with 2M NaOH and diluted with DCM. The organic phase was collected using a Telos phase separator and evaporated to dryness under reduced pressure to give the title compound as an orange oil (840 mg, 69%).

The method B comprises the following steps: LC-MS (electrospray): m/z =217/219 (M + H) ⁺ RT =1.22 min

And step 3: n- [ (3-bromo-5-methoxy-2-pyridinyl) methyl ] carbamic acid tert-butyl ester

A mixture of (3-bromo-5-methoxy-2-pyridyl) methylamine (830mg, 3.82mmol), boc anhydride (1001mg, 4.59mmol) and triethylamine (1.3mL, 9.56mmol) in acetonitrile (26 mL) was stirred at reflux for 1 hour. The mixture was evaporated to dryness, then water was added and the mixture was extracted with DCM using a Telos phase separator. The organics were evaporated to dryness to give the title compound as a brown oil (1130 mg, 75%).

The method A comprises the following steps: LC-MS (electrospray): m/z =317/319 (M + H) ⁺ RT =1.20 min

And 4, step 4: 8-bromo-6-methoxy-imidazo [1,5-a ] pyridine

Reacting N- [ (3-bromo-5-methoxy-2-pyridyl) methyl group]A mixture of t-butyl carbamate (500mg, 1.58mmol), trimethoxymethane (8.6mL, 78.8mmol) and TFA (0.47mL, 6.31mmol) inStirring was carried out at 100 ℃ for 0.5 hour. The mixture was evaporated to dryness and passed through SiO ₂ Purification by upper chromatography (0% to 100% EtOAc in heptane, followed by elution with 10% meoh in EtOAc) to give the title compound as a light viscous solid (191mg, 53%).

The method A comprises the following steps: LC-MS (electrospray): m/z =227/229 (M + H) ⁺ RT =0.80 min

And 5:2- (6-methoxyimidazo [1,5-a ] pyridin-8-yl) ethynyl-trimethyl-silane

Reacting 8-bromo-6-methoxy-imidazo [1,5-a]Pyridine (790mg, 3.48mmol), ethynyl (trimethyl) silane (0.98mL, 6.96mmol), pdCl ₂ A mixture of (dppf) (255mg, 0.348mmol), triethylamine (2.4mL, 17.4mmol) and CuI (66mg, 0.348mmol) in dry DMF (5 mL) was stirred at 100 ℃ for 2 hours. The mixture was cooled to room temperature, diluted with EtOAc (25 mL) and filtered through celite. The filtrate was evaporated to dryness and passed through SiO ₂ Purification by upper chromatography (elution with 0% to 100% etoac in heptane) to give the title compound as a brown oil (250mg, 25%).

The method A comprises the following steps: LC-MS (electrospray): m/z =245.1 (M + H) ⁺ RT =1.11 min

And 6: 8-ethynyl-6-methoxy-imidazo [1,5-a ] pyridine

Potassium carbonate (163mg, 1.18mmol) was added to 2- (6-methoxyimidazo [1,5-a at ambient temperature]Pyridin-8-yl) ethynyl-trimethyl-silane (90%, 160mg,0.589 mmol) in MeOH (2.75 mL) and the mixture stirred at ambient temperature for 1 h. The solvent was removed under reduced pressure. Is added in CHCl ₃ 25% of IPA (30 mL) and water (30 mL), and collecting the organic phase using a Telos phase separatorAnd concentrated under reduced pressure to give the title compound as a brown oil (90mg, 63%).

The method A comprises the following steps: LC-MS (electrospray): m/z =173.1 (M + H) ⁺ RT =0.77 min

And 7:2- [ [ tert-Butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- (6-methoxyimidazo [1,5-a ] pyridin-8-yl) triazol-1-yl ] methyl ] indole-1-carboxylic acid tert-butyl ester

Mixing 8-ethynyl-6-methoxy-imidazo [1,5-a]Pyridine (70mg, 0.407mmol), 6- (azidomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino]Methyl radical]Indole-1-carboxylic acid tert-butyl ester (191mg, 0.407mmol) (intermediate 7), cuSO ₄ A mixture of (13mg, 0.0813mmol) and sodium ascorbate (89mg, 0.447mmol) in DMF (4.5 mL) and water (1 mL) was stirred at ambient temperature overnight. The mixture was diluted with water and DCM and the organic phase was collected using a Telos phase separator. The organics were evaporated to dryness under reduced pressure and passed through SiO ₂ Purification by chromatography (KP-NH; 0% to 100% EtOAc in heptane, followed by 0% to 20% meoh in EtOAc) to give the title compound as an orange solid (120mg, 46%).

Method J: LC-MS (electrospray): m/z =642.5 (M + H) ⁺ RT =0.82 min

And 8: n- (cyclobutylmethyl) -1- [6- [ [4- (6-methoxyimidazo [1,5-a ] pyridin-8-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine

HCl (4M in dioxane, 0.47ml, 1.87mmol) was added to a solution of tert-butyl 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- (6-methoxyimidazo [1,5-a ] pyridin-8-yl) triazol-1-yl ] methyl ] indole-1-carboxylate (120mg, 0.187mmol) in DCM (1.2 mL) and the mixture was stirred at room temperature for 16 h. The mixture was evaporated to dryness and purified by preparative HPLC (method B). The product-containing fractions were combined and the organic solvent was removed under reduced pressure. The solid thus obtained formed in the aqueous suspension was collected by vacuum filtration and dried under vacuum to obtain the title compound (26mg, 31%) as a white powder.

The method C comprises the following steps: LC-MS (electrospray): m/z =442.4 (M + H) ⁺ RT =3.28 min

Intermediate 8: 1-tert-butyl 2-methyl 6- (bromomethyl) -1H-indole-1,2-dicarboxylate

Step 1: 1-tert-butyl 2-methyl 6-methyl-1H-indole-1,2-dicarboxylate

Methyl 6-methyl-1H-indole-2-carboxylate (5.25g, 27.7 mmol) and DMAP (0.53g, 4.30mmol) were combined in acetonitrile (80 mL) and Boc was added ₂ O (7.27g, 33.3mmol). The reaction was stirred at ambient temperature for 10 minutes at which time the solution changed color from colorless to dark orange. The temperature was raised to 45 ℃ and stirred overnight. The mixture was cooled to room temperature and the solvent was removed in vacuo to give an orange solid. The solid was dissolved in EtOAc (150 mL) and washed with water (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The combined organic phases were washed with brine (100 mL) and Na ₂ SO ₄ Dried and evaporated under vacuum to give the crude material as an orange residue. Passing the residue through SiO ₂ Purification by chromatography on (100 g Kp-Sil, eluting with EtOAc/heptane 0% to 50%) afforded the title compound as an off-white crystalline solid (8.20g, 100%).

Step 2: 1-tert-butyl 2-methyl 6- (bromomethyl) indole-1,2-dicarboxylate

1-tert-butyl O2-methyl 6-methylindole-1,2-dicarboxylate (5.00g, 17.3mmol), 1-bromopyrrolidine-2,5-dione (2.92g, 16.4 mmol) and AIBN (284mg, 1.73mmol) were combined in DCE (200 mL) and the mixture was stirred at 75 ℃ for 2 hours. The mixture was cooled to room temperature and concentrated in vacuo. Passing the residue through SiO ₂ Purify by chromatography (0% to 10% etoac/heptane, KP-sil,30g, in 2 batches), combine the clean fractions and concentrate to give the title compound as a colourless oil which forms a white crystalline solid on standing (4.00g, 61%).

The method B comprises the following steps: LC-MS (electrospray): m/z =368.1/370.1 (M + H) ⁺ RT =2.00 min

Intermediate 9:4- (1H-imidazol-4-yl) -1-tetrahydropyran-2-yl-indazole

Step 1: 4-bromo-1-tetrahydropyran-2-yl-indazoles

4-bromo-1H-indazole (6.1g, 31.0mmol) and toluenesulfonic acid monohydrate (589mg, 3.10mmol) were combined in DCM (100 mL) and 3,4-dihydro-2H-pyran (4.24mL, 46.4mmol) was added. The mixture was stirred at ambient temperature for 3 hours. The mixture was washed with saturated NaHCO ₃ (aqueous solution) (100 mL) and the mixture was stirred vigorously for 5 minutes. The layers were separated, the aqueous layer was extracted with DCM (2X 100 mL), and the combined organic layers were washed with Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Purification by chromatography (100 g kp-Sil, eluting with EtOAc/heptane 0% to 100%) afforded the title compound as a white solid (8.91g, 96%).

The method A comprises the following steps: LC-MS (electrospray): m/z =280.9/282.9 (M + H) ⁺ RT =1.31 min

Step 2: 1-tetrahydropyran-2-yl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indazole

4-bromo-1-tetrahydropyran-2-yl-indazole (3 g, 10.7mmol), potassium acetate (4.76g, 48.0mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxazapentaborane-2-yl) -1,3,2-dioxazapentaborane (3.52g, 13.9mmol) and PdCl ₂ (dppf) (391mg, 0.53mmol) was combined in 1,4-dioxane (40 mL) and the mixture was bubbled with nitrogen for 5 minutes. The mixture was heated under nitrogen at 100 ℃ (external) for 2.5 hours. The mixture was cooled to room temperature, diluted with EtOAc (150 mL) and filtered. The residue was washed with EtOAc and the combined filtrates were washed with saturated NaHCO ₃ (aqueous) (100 mL) and brine (100 mL). Subjecting the organic layer to Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Purification by chromatography on (100 g kp-Sil, eluting with EtOAc/heptane 0% to 100%) afforded the title compound as a light yellow wax (3.21g, 78).

The method A comprises the following steps: LC-MS (electrospray): m/z =329.2 (M + H) ⁺ RT =1.39 min

And step 3:4- (1H-imidazol-4-yl) -1-tetrahydropyran-2-yl-indazole

1 to (

Alk-2-yl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole (740mg, 2.25mmol), 4-bromo-1H-imidazole (440mg, 2.93mmol), pd (OAc) ₂ (101mg, 0.45mmol), APhos (287mg, 1.08mmol) and K ₂ CO ₃ (aqueous solution) (1.2M aqueous solution, 5.6mL, 6.76mmol) was combined in 1,4-dioxane (10 mL) and the mixture was bubbled with nitrogen for 5 minutes. The vessel was sealed and the mixture was heated at 115 ℃ (external) for 2.5 hours. The mixture was cooled to room temperature and left overnight. The mixture was diluted with water (80 mL) and extracted with 3:1 chloroform/isopropanol (3X 50 mL). The combined organic extracts are passed over Na ₂ SO ₄ Dried and evaporated under vacuum. The residue is passed through (SiO) ₂ Purification by chromatography (kp-NH eluting with EtOAc/heptane 0% to 100% followed by MeOH/EtOAc 0% to 20%) gave the title compound as a white solid (371mg, 58%).

The method B comprises the following steps: LC-MS (electrospray): m/z =296.2 (M + H) ⁺ RT =1.35 min

Example 64: n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) imidazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine

Step 1: o1-tert-butyl O2-methyl 6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) imidazol-1-yl ] methyl ] indole-1,2-dicarboxylate

4- (1H-imidazol-4-yl) -1-tetrahydropyran-2-yl-indazole (370mg, 1.38mmol) (intermediate 9), O1-tert-butyl O2-methyl 6- (bromomethyl) indole-1,2-dicarboxylate (508mg, 1.38mmol) (intermediate 8), cs ₂ CO ₃ (5999mg, 2.76mmol) and NaI (21mg, 0.14mmol) were combined in DMF (10 mL) and the mixture was heated (externally) at 90 ℃. The mixture was cooled to room temperature, diluted with EtOAc (50 mL) and saturated NaHCO ₃ (aqueous) (30 mL) and brine (5X 30 mL). Subjecting the organic layer to Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Chromatograph (25 g Sfar Duo, eluting with EtOAc/heptane 0% to 100%, then MeOH/EtOAc 0% to 20%) pureTo give the title compound as a pale orange solid (336mg, 21%).

The method B comprises the following steps: LC-MS (electrospray): m/z =556.3 (M + H) ⁺ RT =1.89 min

Step 2:2- (hydroxymethyl) -6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) imidazol-1-yl ] methyl ] indole-1-carboxylic acid tert-butyl ester

Reacting O1-tert-butyl O2-methyl 6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) imidazol-1-yl]Methyl radical]Indole-1,2-dicarboxylate (336mg, 0.60mmol) was dissolved in anhydrous DCM (10 mL) and cooled to-40 deg.C (external). DIBAL (1M in DCM, 1.21mL, 1.21mmol) was added dropwise and the mixture was stirred at-40 ℃ for 1 hour. DIBAL (1M in DCM, 1.21mL, 1.21mmol) was added and the mixture was stirred for 3 hours. DIBAL (1M in DCM, 1.21mL, 1.21mmol) was added and the mixture was stirred for 5 h. The mixture was quenched by dropwise addition of MeOH (4 mL) and the mixture was stirred for 5 minutes under cooling, then allowed to warm to room temperature. The mixture was further diluted with 2M NaOH (aq) (4 mL), followed by water (10 mL), and the mixture was left overnight. The phases were separated and the aqueous phase was extracted with DCM (3X 30 mL). The combined organic layers were passed over Na ₂ SO ₄ Dried and evaporated in vacuo to give the title product as a brown residue (343mg, 45%), which was used without further purification.

The method B comprises the following steps: LC-MS (electrospray): m/z =528.3 (M + H) ⁺ RT =1.73 minutes

And step 3: 2-formyl-6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) imidazol-1-yl ] methyl ] indole-1-carboxylic acid tert-butyl ester

Reacting 2- (hydroxymethyl) -6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) imidazol-1-yl]Methyl radical]Indole-1-carboxylic acid tert-butyl ester (C: (C)) 343mg, 0.65mmol) in DCE (N-dimethylformamide)10 mL) and MnO was added ₂ (565mg, 6.50mmol). The mixture was heated at reflux for 1 hour. Adding additional amounts of MnO ₂ (565mg, 6.50mmol) and continued to reflux for another 2 hours. The mixture was cooled to room temperature and filtered through a plug of celite. The residue was washed with MeOH, and the combined filtrates were evaporated in vacuo to give the title compound as a pale yellow solid compound (233mg, 40%). The material was used without purification.

The method B comprises the following steps: LC-MS (electrospray): m/z =526.3 (M + H) ⁺ RT =1.88 min

And 4, step 4: n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) imidazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine

Reacting 2-formyl-6- [ [4- (1-tetrahydropyran-2-ylidazol-4-yl) imidazol-1-yl ]Methyl radical]Indole-1-carboxylic acid tert-butyl ester (230mg, 0.44mmol) and 1-cyclobutylmethylamine (75mg, 0.88mmol) were combined in 1,1,1,3,3,3-hexafluoro-2-propanol (5 mL) and the mixture was incubated at ambient temperature for 30 minutes. To NaBH ₄ (50mg, 1.31mmol) A few drops of MeOH were added and the mixture was stirred briefly at ambient temperature. The mixture was quenched with MeOH, and the mixture was evaporated under vacuum. The residue was taken up in saturated NaHCO ₃ (aq) (20 mL) was partitioned and extracted with DCM (3X 30 mL). The combined organic extracts are passed over Na ₂ SO ₄ Dried and evaporated under vacuum. The residue was redissolved in MeOH (5 mL) and 4M HCl in dioxane (5 mL) and the mixture was heated at 60 ℃ (external) for 3 hours. The mixture was cooled to room temperature and evaporated under vacuum. The residue was loaded onto a SCX-2 column (5 g), and the column was washed with DCM and MeOH, followed by 7M NH ₃ MeOH elution. The basic eluent was evaporated under vacuum. The crude material was purified by preparative HPLC (method B) and the fractions containing clean product were combined and evaporated in vacuo to give the title compound as a beige solid (19mg, 11%).

The method D comprises the following steps: LC-MS (electrospray): m/z＝411.3(M+H) ⁺ RT =4.13 min

Intermediate 10: n' -hydroxy-1-tetrahydropyran-2-yl-indazole-4-carboxamidine

Step 1: 4-bromo-1-tetrahydropyran-2-yl-indazoles

4-bromo-1H-indazole (8g, 40.6mmol), toluenesulfonic acid monohydrate (772mg, 4.06mmol) and 3,4-dihydro-2H-pyran (5.56mL, 60.9 mmol) were combined in DCM (80 mL) and the mixture was stirred at ambient temperature for 3 hours. The mixture was washed with saturated NaHCO ₃ (aqueous solution) (80 mL) quench and stir vigorously for 5 minutes. The phases were separated, the aqueous phase was extracted with DCM (2X 50 mL), and the combined organic layers were washed with Na ₂ SO ₄ Drying was evaporated under vacuum. Passing the residue through SiO ₂ Chromatography (350 g Sfar Duo, eluting with EtOAc/heptane 0% to 100%) to give the title compound as a colourless oil which solidified to a white wax on standing (11.16g, 97%).

The method B comprises the following steps: LC-MS (electrospray): m/z =281.1/283.1 (M + H) ⁺ RT =1.83 min

Step 2: 1-tetrahydropyran-2-ylidazole-4-carbonitrile

Oven-dried three-necked 25mL RBF was charged with zinc cyanide (459mg, 3.91mmol), 4-bromo-1-tetrahydropyran-2-yl-indazole (1.00g, 3.56mmol), palladium-triphenylphosphine complex (1:4) (206mg, 0.178mmol), and anhydrous DMF (9 mL). The flask was equipped with a reflux condenser, the assembly was flushed with nitrogen, and the mixture was subsequently deoxygenated by passing a stream of nitrogen over 5 minutes. Placing the mixture in a preheated heating block at 100 ℃ and reacting the reactants Stirred at this temperature for 3 hours. The mixture was cooled to room temperature and diluted with EtOAc (30 mL) and water (20 mL). The aqueous phase was extracted with EtOAc (2X 30 mL). The combined organics were washed with brine (10 mL), dried over magnesium sulfate and concentrated to give a reddish oily solid. By SiO ₂ Purification was performed by upper chromatography (Sfar silica duo 25g column) eluting in a gradient of EtOAc/heptane (0% to 100%). The product-containing fractions were combined to give the title compound (697mg, 86%) as a white solid.

The method B comprises the following steps: LC-MS (electrospray): m/z =228.3 (M + H) ⁺ RT =1.60 min

And step 3: n' -hydroxy-1-tetrahydropyran-2-yl-indazole-4-carboxamidine

1-Tetrahydropyran-2-ylindazole-4-carbonitrile (100mg, 0.440mmol), ethanol (5 mL), and 17M hydroxylamine (50% in water) (0.13mL, 2.20mmol) were combined and heated at 80 ℃ at reflux for 3.5 hours. The mixture was cooled to room temperature and concentrated. The resulting solid was washed with water (about 5 mL) and air-dried to give a white solid. By SiO ₂ Purification was performed by upper chromatography (10 g sfar duo column) eluting in a gradient of EtOAc/heptane 0% to 100%. The product-containing fractions were combined to give the title compound as an off-white solid (93mg, 77%).

The method B comprises the following steps: LC-MS (electrospray): m/z =261.2 (M + H) ⁺ RT =1.26 min

Intermediate 11:2- (1H-indol-6-yl) acetic acid

Step 1: 6-Formylindole-1-carboxylic acid tert-butyl ester

1H-indole-6-carbaldehyde (4.52g, 31.14mmol) and Boc were added ₂ O (8.15g, 37.4 mmol) and DMAP (380mg, 3.11mmol) were combined in acetonitrile (50 mL), and the mixture was heated at reflux for 1 hour. The mixture was cooled to room temperature and evaporated under vacuum. The residue was redissolved in EtOAc (150 mL) and treated with saturated NaHCO ₃ (aq) (2X 80 mL) and brine (80 mL). Subjecting the organic layer to Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Purification by chromatography on (100 g of Sfar Duo, eluting with EtOAc/heptane 0% to 100%) afforded the title compound as a light yellow solid (7.53g, 95%).

The method A comprises the following steps: LC-MS (electrospray): m/z =246.0 (M + H) ⁺ RT =1.33 min

Step 2:2- (1H-indol-6-yl) acetonitrile

Mixing KO with water _t Bu (906 mg, 8.07mmol) was suspended in anhydrous THF (25 mL) and cooled to-55 deg.C (external). Slowly adding 1- [ (isocyanomethyl) sulfonyl group]A solution of 4-methylbenzene (TosMIC; 946mg, 4.48mmol) in anhydrous THF (8 mL) and the mixture was stirred for 15 minutes with cooling. A solution of tert-butyl 6-formylindole-1-carboxylate (1g, 4.04mmol) in anhydrous THF (10 mL) was then added dropwise over 15 minutes, ensuring the temperature <At-50 ℃ to give a dark yellow solution and mixing the mixture in<Stirring was carried out at-50 ℃ for 2 hours. MeOH (50 mL) was added and the mixture was heated at reflux for 15 min. The mixture was cooled to room temperature and evaporated under vacuum. The residue was suspended in water (100 mL) and AcOH (4 mL) and extracted with DCM (3X 80 mL). The combined organic extracts are passed over Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Purification by chromatography (25 g of Sfar Duo eluting with EtOAc/heptane 0% to 100%) afforded the title compound as an off-white solid (532mg, 84%).

The method A comprises the following steps: LC-MS (electrospray): m/z = no ionization (M + H) ⁺ RT =1.05 min

And 3, step 3:2- (1H-indol-6-yl) acetic acid

A flask was charged with 2- (1H-indol-6-yl) acetonitrile (508mg, 3.25mmol), IPA (40 mL), and water (40 mL). Lithium hydroxide (4059mg, 0.163mol) was added to the resulting solution. The mixture was stirred at 75 ℃ for 25 hours and occasionally solids deposited above the solvent level were reintroduced into the reaction. The mixture was cooled in an ice bath and neutralized with 1M HCl solution until pH 4 to 5. The reaction was treated with IPA/CHCl ₃ 5363A mixture of 1:3 (4X 50 mL) was extracted. The combined organics were dried over magnesium sulfate and concentrated to give a pink solid. By SiO ₂ Purification was performed by upper chromatography (25 g sfar duo) eluting in a gradient of DCM/MeOH 0% to 33%. The product-containing fractions were collected to give the title compound (407mg, 69%) as a yellow solid.

The method L comprises the following steps: LC-MS (electrospray): m/z =176.0 (M + H) ⁺ RT =0.6 min

Intermediate 13: +/-1- { 3-fluorobicyclo [1.1.1] pentan-1-yl } ethan-1-amine

Step 1: 3-fluorobicyclo [1.1.1] pentane-1-carboxylic acid

A500 mL three-necked flask was charged with Selectfluor (17.02g, 48.0 mmol), bicyclo [1.1.1]Pentane-1,3-dicarboxylic acid (3.00g, 19.2mmol), silver nitrate (2454mg, 1.44mmol) and water (96 mL), in small volumes, were used to achieve complete transfer of silver nitrate. The reaction was equipped with a reflux condenser connected to an oil bubbler and a submerged thermometer. The reactants were deoxygenated by passing a stream of nitrogen over the contents for 15 minutes. The reaction was kept under a nitrogen stream and placed under a pre-heat addition at 65 deg.C (external)In the thermoblock. The internal temperature of the reactants reached 60 ℃ in about 15 minutes and gas evolution was observed above 50 ℃. The temperature control was adjusted and the internal temperature stabilized at about 62 ℃ to 63 ℃ after another 15 minutes. Stirring was continued at this temperature for 2.5 hours. The reaction was cooled to room temperature and extracted with ether (4X 40 mL). The combined organics were passed over Na ₂ SO ₄ Dried and concentrated under vacuum to a small volume. The resulting oil was allowed to crystallize. The solid was redissolved in a small amount of diethyl ether (about 15 mL) resulting in the separation of a white gel phase. The solution was filtered through a phase separator over Na ₂ SO ₄ Dried and concentrated to give the title compound as a white solid (1.85g, 70%).

The method E comprises the following steps: LC-MS (electrospray): m/z =129.2 (M-H) -, RT =1.44 min

Step 2: 3-fluoro-N-methoxy-N-methylbicyclo [1.1.1] pentane-1-carboxamide

An oven-dried 25mL flask was charged with 3-fluorobicyclo [1.1.1]Pentane-1-carboxylic acid (359 mg, 2.62mmol), purged with nitrogen and added DCE (5 mL) and anhydrous DMF (18.032 μ L), resulting in a clear solution. N-methoxy methylamine hydrochloride (1.3g, 13.1mmol) was added slowly to the solution, resulting in gas evolution. The reaction was stirred at room temperature for 4 hours and then cooled in ice. Oxalyl chloride (0.45ml, 5.24mmol) was added (additional gas evolved) followed by slow addition of N-ethyl-N-isopropyl-propan-2-amine (4.6ml, 26.2mmol) and the reaction stirred at room temperature for 24 h. The mixture was diluted with DCM (20 mL) and washed with water (5 mL) and brine (5 mL) over Na ₂ SO ₄ Dried and concentrated to give a brown oil (about 1.3 g). This material was redissolved in DCM (25 mL), washed with HCl (1M, 5 mL), water (5 mL) and brine (5 mL), and passed over Na ₂ SO ₄ Dried and concentrated to give a brown oil (700 mg). Passing the material through SiO ₂ Chromatography [ elution with 0% to 100% EtOAc/heptane]Followed by 0% to 100% MeOH/EtOAc to obtainThe title compound (347mg, 73%) was obtained as a yellow oil.

Method J: LC-MS (electrospray): m/z =174.2 (M-H) -, RT =0.50 min

And step 3:1- (3-fluoro-1-bicyclo [1.1.1] pentyl) ethanone

Reacting 3-fluoro-N-methoxy-N-methyl-bicyclo [ 1.1.1%]A cooled (0 ℃) solution of pentane-1-carboxamide (130mg, 0.71mmol) in anhydrous THF (2 mL) was slowly treated with methylmagnesium bromide (1M in THF, 1.1mL,1.1 mmol) resulting in the formation of a cloudy solution, which was stirred at 0 ℃ to 5 ℃ for 4 hours and then treated with additional methylmagnesium bromide (1M in THF, 1.1mL,1.1 mmol), and the reaction was stirred for 1 hour and then with NH ₄ Cl (saturated, 2 mL) was quenched and warmed to room temperature. The mixture was extracted with diethyl ether (20+10mL), and the combined organics were passed over Na ₂ SO ₄ The bed was filtered and concentrated in vacuo (at room temperature) to give the title compound as a yellow oil (130mg, 87%).

¹ H NMR(400MHz，DMSO)δ2.31(d，J＝2.7Hz，6H)，2.15(s，3H)

And 4, step 4:1- (3-fluoro-1-bicyclo [1.1.1] pentyl) ethylamine hydrochloride

1- (3-fluoro-1-bicyclo [1.1.1] ]A solution of pentyl) ethanone (130mg, 0.62mmol), ammonium acetate (954mg, 12.4mmol) and sodium cyanoborohydride (389mg, 6.2mmol) in MeOH (2 mL) was stirred at room temperature for 20 h. The mixture was diluted with water (3 mL) and CHCl ₃ IPA (3. The aqueous phase was saturated with sodium chloride and CHCl ₃ Extract with/IPA (3:1, 10 mL). The combined organics were washed with a mixture of water (1 mL) and brine (5 mL) and washed with Na ₂ SO ₄ And (5) drying. The resulting solution was cooled using an ice bath and washed with HCl (4M in dioxane,4 mL). The mixture was allowed to warm and stir for 3 hours, then concentrated to give a yellow residue (104 mg). This material was dissolved in ethanol (2 mL) and diethyl ether (50 mL) was added. The resulting suspension was stirred for 5 minutes and filtered to give the title compound as a white solid (36mg, 33%).

Method K: LC-MS (electrospray): m/z =129.95 (M + H) ⁺ RT =0.45 min

Intermediate 14: 8-Bromoimidazo [1,5-a ] pyridines

A mixture of formaldehyde (37%, 16mL, 0.22mol) and ammonium acetate (20.7g, 0.27mol) in acetic acid (100 mL) was stirred at room temperature for 10 minutes, followed by the addition of 3-bromopyridine-2-carbaldehyde (5.0g, 26.9 mmol) in portions over 2 hours and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between water (100 mL) and DCM (100 mL) and the phases were separated. The aqueous phase was washed with DCM (3 × 100 mL) and the combined organic phases were passed through an Isolute phase separator and concentrated in vacuo. Passing the residue through SiO ₂ Purification by chromatography (eluting with 0% to 100% etoac/heptane) to give the title compound as an off-white solid (2.51g, 46%).

The method C comprises the following steps: LC-MS (electrospray): m/z =196.9/198.9 (M + H) ⁺ RT =2.28 min

Intermediate 15:6- (Azidomethyl) -2- ({ [ (tert-butoxy) carbonyl ] ({ 3-fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino } methyl) -1H-indole-1-carboxylic acid tert-butyl ester

The title compound was prepared from 1- { 3-fluorobicyclo [1.1.1] pentan-1-yl } methylamine hydrochloride in analogy to the procedure described for intermediate 2 and intermediate 7 to give (72mg, 25%) as a cloudy grey oil.

Method J: LC-MS (electrospray): m/z =500.6 (M + H) ⁺ RT =1.17 min

Intermediate 16: n- ({ 2-formyl-1H-pyrrolo [3,2-c ] pyridin-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

Step 1: 4-amino-5-bromo-pyridine-2-carbonitrile

To a solution of 4-aminopyridine-2-carbonitrile (3.25g, 27.3mmol) in acetic acid (30 mL) and acetonitrile (30 mL) were added benzyltrimethylammonium tribromide (10.64g, 27.3mmol) and potassium acetate (5.41g, 54.6 mmol) at room temperature and the mixture was stirred for 24 hours. By adding Na ₂ SO ₃ The solution (saturated, 2 mL) quenched the mixture (color changed from orange to yellow). The mixture was concentrated to dryness under reduced pressure. The residue was washed with EtOAc (200 mL) and Na ₂ CO ₃ (saturated, 100 mL). The organic layer was separated, washed with brine (100 mL) and dried (Na) ₂ SO ₄ ) And concentrated under reduced pressure. Passing the residue through SiO ₂ Purification by chromatography (elution with 0% to 50% etoac in DCM) to give the title compound as a beige solid (2.15g, 39%).

The method C comprises the following steps: LC-MS (electrospray): m/z =197.9/199.9 (M + H) ⁺ RT =1.85 min

Step 2: 4-amino-5- (3,3-diethoxyprop-1-ynyl) pyridine-2-carbonitrile

4-amino-5-bromo-pyridine-2-carbonitrile (480mg, 2.42mmol), 3,3-diethoxyprop-1-yne (0.42mL, 2.91mmol), triethylamine (5.7mL, 41.2mmol), triphenylphosphine (13mg, 0.049mmol), pdCl ₂ (PPh ₃ ) ₂ (17mg, 0.024mmol) and CuI (9).2mg,0.049 mmol) in dry DMF (3.1 mL) was stirred at 80 ℃ for 18 h. More PdCl was added ₂ (PPh ₃ ) ₂ (17mg, 0.024mmol) and CuI (9.2mg, 0.049mmol) and the mixture was stirred at 80 ℃ for 2 h. More 3,3-diethoxypropyne (0.2 mL) was added and the mixture was stirred at 80 ℃ for 2 hours. More 3,3-diethoxypropyne (0.4 mL) was added and the mixture was stirred at 80 ℃ for 18 hours. The mixture was cooled to room temperature, filtered by vacuum filtration to remove the precipitate and washed with EtOAc (25 mL). The organic filtrate was washed with water (25 mL), naHCO ₃ (sat, 3X 25 mL) and brine (25 mL) and dried over magnesium sulfate. The solid residue in the filtrate was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure. Passing the crude material through SiO ₂ Purification by upper chromatography (eluting with 0% to 50% etoac in heptane) to give the title compound as a brown solid (310mg, 43%).

The method A comprises the following steps: LC-MS (electrospray): m/z =246.1 (M + H) ⁺ RT =1.05 min

And step 3:2- (diethoxymethyl) -1H-pyrrolo [3,2-c ] pyridine-6-carbonitrile

Potassium tert-butoxide (235mg, 2.10mmol) was added to a solution of 4-amino-5- (3,3-diethoxyprop-1-ynyl) pyridine-2-carbonitrile (310mg, 1.05mmol) in anhydrous NMP (3.2 mL), and the mixture was stirred at 60 ℃ for 2 hours. The mixture was partitioned between EtOAc (25 mL) and water (25 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (25 mL). The combined organics were washed with brine (3 × 30 mL), dried over magnesium sulfate, filtered and evaporated to dryness to give the title compound as a brown oil (365mg, 99%).

Method J: LC-MS (electrospray): m/z =246.2 (M + H) ⁺ RT =0.65 min

And 4, step 4: 6-cyano-2- (diethoxymethyl) pyrrolo [3,2-c]Pyridine-1-carboxylic acid tert-butyl ester

Boc anhydride (273mg, 1.25mmol) was added to 2- (diethoxymethyl) -1H-pyrrolo [3,2-c]Pyridine-6-carbonitrile (365mg, 1.04mmol) and DMAP (25mg, 0.2mmol) as a solution in acetonitrile (8 mL) and the mixture was stirred at room temperature for 18 h. The mixture was evaporated to dryness in NaHCO ₃ (saturated, 10 mL), water (20 mL) and extracted with DCM (3X 20 mL) using a Telos phase separator. The combined organics were evaporated to dryness and passed through SiO ₂ Purification by chromatography (elution with 0% to 60% etoac in heptane) to give the title compound as a colourless oil (300mg, 0.851mmol, 82%).

The method A comprises the following steps: LC-MS (electrospray): m/z =346.1 (M + H) ⁺ RT =1.40 min

And 5:6- (aminomethyl) -2- (diethoxymethyl) pyrrolo [3,2-c]Pyridine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 6-cyano-2- (diethoxymethyl) pyrrolo [3,2-c ] pyridine-1-carboxylate (300mg, 0.87mmol) and Raney's nickel (ca 51mg, 0.87mmol) in ammonia in MeOH (7M, 0.87mL,6.0 mmol) and ethanol (5.5 mL) was stirred at room temperature under a hydrogen atmosphere for 18 hours. The catalyst was removed by filtration and washed with EtOH (50 mL). The filtrate was evaporated to dryness to give the title compound as a colorless oil (195mg, 45%).

The method A comprises the following steps: LC-MS (electrospray): m/z =350.1 (M + H) ⁺ RT =0.92 min

Step 6:2- (diethoxymethyl) -6- [ [ (4-oxopyrido [1,2-a ] pyrimidine-2-carbonyl) amino ] methyl ] pyrrolo [3,2-c ] pyridine-1-carboxylic acid tert-butyl ester

Mixing 4-oxo-pyrido [1,2-a]Pyrimidine-2-carboxylic acid intermediate 1 (116mg, 0.61mmol) was added to 6- (aminomethyl) -2- (diethoxy)Ylmethyl) pyrrolo [3,2-c]Pyridine-1-carboxylic acid tert-butyl ester (190mg, 0.54mmol), T3P (50% in EtOAc, 0.39mL, 0.65mmol) and DIPEA (0.28mL, 1.63mmol) in DMF (2.5 mL) and the mixture was stirred at room temperature for 1 h. The mixture was partitioned between EtOAc (25 mL) and water (25 mL). The aqueous phase was basified to about pH 10 using NaOH (1M) and the organic phase was collected. The basic aqueous phase was extracted with EtOAc (2X 25 mL). The combined organics were washed with brine (2 × 25 mL), dried over magnesium sulfate and evaporated to dryness under reduced pressure. Passing the crude material through SiO ₂ Purification by upper chromatography (0% to 100% EtOAc in heptane, followed by elution with 0% to 20% meoh in EtOAc) to give the title compound as a colorless oil (250mg, 43%).

The method A comprises the following steps: LC-MS (electrospray): m/z =522.1 (M + H) ⁺ RT =1.01 min

And 7: n- ({ 2-formyl-1H-pyrrolo [3,2-c ] pyridin-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

TFA (2.7mL, 36.8mmol) was added to a solution of tert-butyl 2- (diethoxymethyl) -6- [ [ (4-oxopyrido [1,2-a ] pyrimidine-2-carbonyl) amino ] methyl ] pyrrolo [3,2-c ] pyridine-1-carboxylate (240mg, 0.46mmol) in DCM (2.5 mL) and the mixture was stirred at room temperature for 1 hour.

The mixture was evaporated to dryness and the residue was suspended in water (2 mL) and basified to about pH 10 using NaOH (1M). The aqueous mixture was evaporated to dryness under reduced pressure. The residue was suspended in MeCN (5 mL) and the precipitate formed was collected by vacuum filtration, washed with water (3 mL) and dried under vacuum to give (133mg, 83%) as a brown solid.

The method A comprises the following steps: LC-MS (electrospray): m/z =348.0 (M + H) ⁺ RT =0.69 min

Intermediate 17: 5-amino-6-bromo-pyridine-3-carbonitrile

N-bromosuccinimide (3287mg, 18.5 mmol) was added to a solution of 5-aminopyridine-3-carbonitrile (2000mg, 16.8mmol) in anhydrous DMF (20 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic phase was washed with water (100 mL) and brine (2 × 100 mL), dried over magnesium sulfate and evaporated to dryness. Passing the crude material through SiO ₂ Purification by upper chromatography (eluting with 0% to 100% etoac in heptane) to give the title compound as a yellow solid (460mg, 14%).

¹ H NMR(500MHz，DMSO)δ7.97(d，J＝2.1Hz，1H)，7.36(d，J＝2.1Hz，1H)，6.08(s，2H)

Intermediate 18: n- ({ 2-formyl-1H-pyrrolo [3,2-c ] pyridin-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

The title compound was prepared from intermediate 17 in analogy to intermediate 16, to yield (185mg, 86%) as a light brown solid.

The method A comprises the following steps: LC-MS (electrospray): m/z =348.0 (M + H) ⁺ RT =0.76 min

Intermediate 19:6- (bromomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] indole-1-carboxylic acid tert-butyl ester

Reacting 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] group]Methyl radical]Tert-butyl (6- (hydroxymethyl) indole-1-carboxylate intermediate 7 step 4 (1g, 2.25mmol) and tetrabromomethane (2.24g, 6.75mmol) were combined in THF (30 mL) and triphenylphosphine (1.77g, 6.75mmol) was added. A color change to orange-yellow was observed within 2 minutes and a precipitate formed. The mixture was heated at 55 ℃ for 2 hours. Cooling the mixtureIt was filtered to room temperature and the residue was washed with THF and the combined filtrates were evaporated in vacuo. Passing the residue through SiO ₂ Purification by upper chromatography (eluting with 0% to 100% TBME/heptane) to give the title compound (452 mg,%) as a colourless residue.

The method A comprises the following steps: LC-MS (electrospray): m/z =529.2/531.2 (M + H) ⁺ RT =2.06 min

Intermediate 20: 4-Bromoimidazol-1-carboxylic acid tert-butyl ester

4-bromo-1H-imidazole (2g, 13.3mmol), DMAP (163mg, 1.33mmol) and Boc ₂ O (3.78g, 17.3 mmol) was combined in THF (20 mL) (note gas evolution) and the mixture was stirred at room temperature for 3 hours. The mixture was evaporated under vacuum and the residue was passed through SiO ₂ Purification by upper chromatography (eluting with 0% to 100% etoac/heptane) to give the title compound as a colourless oil which solidified to a white waxy solid on standing (3.04g, 92%).

The method B comprises the following steps: LC-MS (electrospray): m/z =247.2/249.2 (M + H) ⁺ RT =1.60 min

Intermediate 21: n- [ (2-formyl-1H-indol-6-yl) methyl ] -1H-pyrrolo [2,3-b ] pyridine-5-carboxamide

The title compound was prepared from example 2, step 3 in a similar manner as described in example 2, step 4 to give (445mg, 56%) as a pale pink solid.

The method B comprises the following steps: LC-MS (electrospray): m/z =319.2 (M + H) ⁺ RT =1.32 min

Example 66: n- (cyclobutylmethyl) -1- [6- [ [3- (1H-indazol-4-yl) -1,2,4-

Diazol-5-yl]Methyl radical]-1H-indol-2-yl]Methylamine

Step 1:2- [2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -1H-indol-6-yl ] acetic acid

The title compound (62mg, 76%) was prepared in the same manner as intermediate 11 using the precursor from intermediate 7, step 3.

The method C comprises the following steps: LC-MS (electrospray): m/z =373.2 (M + H) ⁺ RT =3.86 min

Step 2: n- (cyclobutylmethyl) -1- [6- [ [3- (1H-indazol-4-yl) -1,2,4-

Diazol-5-yl]Methyl radical]-1H-indol-2-yl]Methylamine

The title compound (7.6 mg, 14%) was prepared in the same manner as in example 64.

The method C comprises the following steps: LC-MS (electrospray): m/z =413.4 (M + H) ⁺ RT =3.71 min

Example 114: n- [ (2- { [ (1-methylcyclopentyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

Reacting N- [ (2-formyl-1H-indol-6-yl) methyl]-4-oxo-pyrido [1,2-a]Pyrimidine-2-carboxamide (70mg, 0.20mmol), 1-methylcyclopentylamine hydrochloride (55mg, 0.40mmol) and triethylamine (83. Mu.L, 0.61 mmol) were added at 1,1,1,3,33-hexafluoro-2-propanol (3 mL) and the mixture was stirred at room temperature for two days. Addition of NaBH ₄ (76mg, 2.02mmol) and several drops of MeOH (gas evolution) and the mixture was stirred briefly. The mixture was quenched with MeOH (gas evolution) and evaporated under vacuum. Suspending the residue in NaHCO ₃ (saturated, 30 mL) and extracted with chloroform/isopropanol (3, 1,3 × 30 mL). The combined organic extracts are passed over Na ₂ SO ₄ Dried and evaporated under vacuum. The residue was purified by preparative HPLC (method B) and the fractions containing the clean product were combined and evaporated in vacuo to give the title compound as a light yellow solid (50mg, 57%).

The method C comprises the following steps: LC-MS (electrospray): m/z =430.7 (M + H) ⁺ RT =3.43 min

Example 115: n- { [2- (hydroxymethyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

The title compound (18mg, 25%) was isolated as an off-white solid during the purification of example 114.

The method C comprises the following steps: LC-MS (electrospray): m/z =349.3 (M + H) ⁺ RT =2.15 min

The compounds in table 3 were prepared in the same manner as in example 114 using a commercial amine or the intermediate.

TABLE 3

Example 121: n- ({ 2- [ (tert-butylamino) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

Tert-butylamine (34. Mu.L, 0.566 mmol) and N- [ (2-formyl-1H-indol-6-yl) methyl]-4-oxo-pyrido [1,2-a]A suspension of pyrimidine-2-carboxamide (100mg, 0.28mmol) in DCE (7 mL) was stirred at 60 ℃ for 65 hours and allowed to stand for one week. The mixture was diluted with ethanol (3 mL) and carefully treated with NaBH ₄ (32mg, 0.85mmol) and stirred for 16 h. The mixture is washed with NaHCO ₃ (saturated, 5 mL), extracted with DCM (3 × 5 mL) and the extract concentrated in vacuo. The residue was purified by preparative HPLC (method B) to give a light gum which was triturated with MeCN to give 28mg of an off-white solid. The solid was recrystallized from MeCN, the solid was collected by filtration and Et ₂ O washed and dried in a vacuum oven to give the title compound as an off-white solid (1695g, 14%).

The method C comprises the following steps: LC-MS (electrospray): m/z =404.5 (M + H) ⁺ RT =3.10 min

Example 123: n- { [2- (2- { 2-azaspiro [3.3] heptan-2-yl } ethyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

Step 1: n- (5-cyano-2-iodophenyl) -2,2,2-trifluoroacetamide

3-amino-4-iodobenzonitrile (3.3g, 13.52mmol) was dissolved in DCM (40 mL) and trifluoroacetic anhydride (5.6 mL, 40.3mmol) was added in a slow stream and the mixture was stirred at room temperature for 1 h. The mixture was evaporated directly onto silica. The solid was deposited on a short pad of silica (diameter about 5cm, depth 5 cm) and eluted with 0% to 100% dcm/heptane to give the title compound as a white solid (4.3g, 93%).

The method B comprises the following steps: LC-MS (electrospray): m/z =358.1 (M + H) ⁺ RT =0.98 min

And 2, step: 2- (2-hydroxyethyl) -1H-indole-6-carbonitrile

N- (5-cyano-2-iodo-phenyl) -2,2,2-trifluoro-acetamide (4.3g, 12.14mmol), cuI (231mg, 1.21mmol), and PdCl ₂ (dppf) (888mg, 1.21mmol)) was combined in triethylamine (30 mL) and the mixture was bubbled with nitrogen for 5 minutes, followed by addition of but-3-yn-1-ol (1.84mL, 24.3mmol), the mixture was further bubbled briefly and heated at 70 ℃ under nitrogen for 2 hours. The mixture was cooled to room temperature, diluted with EtOAc (200 mL) and NaHCO ₃ (saturated, 2X 100 mL) and brine (100 mL). Passing the organic phase over Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the obtained residue through SiO ₂ Purification by upper chromatography (eluting with 0% to 100% etoac/heptane) to give the title compound as a beige solid (1.7g, 74%).

The method C comprises the following steps: LC-MS (electrospray): m/z =187.1 (M + H) ⁺ RT =0.65 min

And step 3:2- (6-cyano-1H-indol-2-yl) ethyl 4-methylbenzene-1-sulfonate

4-Methylbenzenesulfonyl chloride (532mg, 2.79mmol) was added to a mixture of 2- (2-hydroxyethyl) -1H-indole-6-carbonitrile (400mg, 2.15mmol) and triethylamine (0.60mL, 4.30mmol) in DCM (26 mL) at 0 deg.C, and the mixture was stirred at 0 deg.C for 20 min and at room temperature for 4H. The mixture was retreated with 4-methylbenzenesulfonyl chloride (532mg, 2.79mmol) and stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and the residue was passed through SiO ₂ Chromatographed to give the title compound as a yellow oil (639mg, 78%) which crystallizes as an off-white solid on standing.

The method A comprises the following steps: LC-MS (electrospray): m/z =341.1 (M + H) ⁺ RT =1.24 min

And 4, step 4:2- [2- (2-azaspiro [3.3 ]]Heptane-2-yl) ethyl]-1H-indole-6-carbonitrile

2- (6-cyano-1H-indol-2-yl) ethyl 4-methylbenzenesulfonate (300mg, 0.881mmol), 2-azaspiro [ 3.3: (mol/mol)]Heptane hydrochloride (0.37ml, 1.32mmol), sodium iodide (1695g, 0.110mmol) and N-ethyl-N- (prop-2-yl) prop-2-amine (0.31ml, 1.76mmol) were combined in DMSO (6.6 mL) and the mixture was stirred at 50 ℃ for 3 hours. The mixture was cooled to room temperature, diluted with EtOAc (20 mL) and NaHCO ₃ (saturated, 20 mL) wash. The white insoluble solid was removed by filtration, the layers were separated, and the mixture was extracted with EtOAc (3 × 20 mL). The organics were washed with brine (50 mL), mgSO ₄ Dried and concentrated under vacuum to a residue which is passed over SiO ₂ Purification by chromatography on (0% to 100% EtOAc/heptane followed by 0% to 20% meoh/EtOAc elution) to give the title compound as an orange oil (62mg, 19%).

The method A comprises the following steps: LC-MS (electrospray): m/z =266.3 (M + H) ⁺ RT =0.86 min

And 5: [2- [2- (2-azaspiro [3.3] heptan-2-yl) ethyl ] -1H-indol-6-yl ] methylamine

2- [2- (2-azaspiro [3.3]]Heptane-2-yl) ethyl]A mixture of-1H-indole-6-carbonitrile (62mg, 0.23mmol) and ammonia in MeOH (7M, 0.61mL, 4.29mmol) in ethanol (2.4 mL) was degassed and Raney nickel (50%, 123mg, 1.04mmol) in H was added ₂ Slurry in O, the mixture was further degassed and stirred under hydrogen atmosphere for 4.5 hours. The mixture was retreated with degassed Raney nickel (50%, 123mg, 1.04mmol) and stirred under hydrogen atmosphere for 16 hThen (c) is performed. The mixture was filtered through celite, washed with MeOH (100 mL) and concentrated to give the title compound as a colorless oil (44mg, 50%).

Method J: LC-MS (electrospray): m/z =270.3 (M + H) ⁺ RT =0.69 min

Step 6: n- { [2- (2- { 2-azaspiro [3.3] heptan-2-yl } ethyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

HATU (85mg, 0.223mmol) was added to 4-oxopyrido [1,2-a]Pyrimidine-2-carboxylic acid intermediate 1 (28mg, 0.15mmol) and DIPEA (0.13ml, 0.74mmol) in DMF (0.6 mL) and the mixture was stirred at room temperature for 10 min. Adding [2- [2- (2-azaspiro [3.3]]Heptane-2-yl) ethyl]-1H-indol-6-yl]Methylamine (40mg, 0.148mmol) and the mixture stirred at room temperature for 90 minutes. The mixture is washed with NaHCO ₃ (sat, 50 mL) and extracted with EtOAc (3X 50 mL). The combined organic phases were washed with water (50 mL) followed by brine (50 mL) and dried (MgSO) ₄ ) And concentrated under vacuum. The crude material was purified by preparative HPLC (method B) to give the title product as an off-white solid (4.1mg, 6.1%).

The method C comprises the following steps: LC-MS (electrospray): m/z =442.7 (M + H) ⁺ RT =3.45 min

Example 124: ({ 3-Fluorobicyclo [1.1.1] pentan-1-yl } methyl) ({ 6- [ (4- { imidazo [1,5-a ] pyridin-8-yl } -1H-1,2,3-triazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine

The title compound was prepared in a similar manner to example 63 using intermediates 14 and 15 to give (7 mg, 31%) as a brown solid.

The method E comprises the following steps: LC-MS (electrospray): m/z =442.2 (M + H) ⁺ RT =1.36 min

Example 125: n- [ (2- { [ ({ 3-Fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -5-oxo-5H- [1,3] thiazolo [3,2-a ] pyrimidine-7-carboxamide

Step 1: n- { [2- (diethoxymethyl) -1H-indol-6-yl ] methyl } carbamic acid tert-butyl ester

2- (diethoxymethyl) -1H-indole-6-carbonitrile (example 2, step 3) (200mg, 0.82mmol), boc anhydride (268mg, 1.23mmol) and NiCl ₂ (11mg, 0.08mmol) were combined in MeOH (5 mL) and NaBH was added in three portions over 3 minutes ₄ (155mg, 4.10 mmol), vigorous gas evolution, black, and the mixture stirred at room temperature for 30 min. Add additional NaBH in portions ₄ (155mg, 4.10 mmol) and the mixture was stirred for 1 hour. The mixture is washed with NaHCO ₃ (sat, 20 mL) and extracted with DCM (3X 30 mL). The combined organic extracts are passed over Na ₂ SO ₄ Dried and evaporated under vacuum. Subjecting the residue to SiO ₂ Purify by chromatography (eluting with 0% to 100% EtOAc/heptane) to give the title compound as a yellow residue (135mg, 43%).

Method J: LC-MS (electrospray): m/z =347.5 (M + H) ⁺ RT =0.87 min

And 2, step: n- [ (2-formyl-1H-indol-6-yl) methyl ] carbamic acid tert-butyl ester

Coupling N- { [2- (diethoxymethyl) -1H-indol-6-yl]Methyl } carbamic acid tert-butyl ester (135mg, 0.39mmol) was dissolved in THF (2 mL), water (2 mL) and acetic acid (2 mL) and stirred at room temperature. Mixing the raw materialsNaHCO for substance use ₃ Basified (saturated) and extracted with DCM (3 × 30 mL). The combined organic extracts are passed over Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Purify by chromatography (eluting with 0% to 100% etoac/heptane) to give the title compound as a white solid (111mg, 98%).

Method J: LC-MS (electrospray): m/z =273.4 (M-H) -, RT =0.72 min

And 3, step 3: n- [ [2- [ [ (3-fluoro-1-bicyclo [1.1.1] pentyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] carbamic acid tert-butyl ester

The title compound was prepared using the procedure described for example 42 to give (92mg, 67%) as a yellow residue.

The method A comprises the following steps: LC-MS (electrospray): m/z =374.2 (M-H) -, RT =0.93 min

And 4, step 4: [2- [ [ (3-fluoro-1-bicyclo [1.1.1] pentyl) methylamino ] methyl ] -1H-indol-6-yl ] methylamine dihydrochloride

The title compound was prepared in a similar manner to example 44, step 3, to give 90mg (quantitative) as a pink solid.

The method A comprises the following steps: LC-MS (electrospray): m/z =274.0 (M + H) ⁺ RT =0.21 min

And 5: n- [ (2- { [ ({ 3-Fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -5-oxo-5H- [1,3] thiazolo [3,2-a ] pyrimidine-7-carboxamide

Reacting 5-oxothiazolo [3,2-a]Pyrimidine-7-carboxylic acid (56mg, 0.28mmol) was added to DIPEA (136. Mu.L, 0.8 mmol) and [2- [ [ (3-fluoro-1-bicyclo [ 1.1.1)]Pentyl) methylamino]Methyl radical]-1H-indol-6-yl]Methylamine dihydrochloride (90mg, 0.26mmol) in a stirred solution of DMF (2 mL) and the mixture stirred at room temperature for 10 min. HATU (108mg, 0.28mmol) in DMF (2 mL) was added and the mixture was stirred at room temperature for 2 h. The mixture is washed with NaHCO ₃ (sat, 25 mL) was partitioned with EtOAc (25 mL) and the layers were separated. The pH of the aqueous layer was adjusted to pH 11 by the addition of NaOH (1M) and the aqueous layer was extracted with EtOAc (3X 25 mL). The combined organic layers were passed over Na ₂ SO ₄ Dried and concentrated under vacuum. The residue was purified by preparative HPLC (method B) to give 11mg of material. The product was further purified by basic preparative HPLC to give the title product as a white solid (5.2mg, 8.4%).

Method a LC-MS (electrospray): m/z =452.5 (M + H) ⁺ RT =3.00 min

Example 126: n- [ (2- { [ ({ bicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-b ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

A mixture of N- [ (2-formyl-1H-pyrrolo [3,2-b ] pyridin-6-yl) methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide (55mg, 0.116mmol), STAB (84mg, 0.4 mmol), and bicyclo [1.1.1] pentan-1-ylmethylamine hydrochloride (23mg, 0.17mmol) in DCE (1.25 mL) was stirred at 50 ℃ for 1 hour. The mixture was evaporated to dryness, dissolved in DMSO (1 mL), filtered and purified by preparative HPLC (method B) to give the title compound as a white solid (24mg, 35%).

Method C LC-MS (electrospray): m/z =429.4 (M + H) ⁺ RT =2.43 min

The compounds in table 4 were prepared from intermediate 16 or intermediate 18 in a similar manner to example 126.

TABLE 4

Example 133: n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H, 6H,7H,8H, 9H-pyrido [1,2-a ] pyrimidine-2-carboxamide

To a degassed solution of N- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide example 2 (150mg, 0.350mmol) in ethanol (25 mL) was added Pd on C (10% Pd (50% wet) 200mg, 0.188mmol) at room temperature. The mixture was degassed again and stirred under hydrogen atmosphere for 6 hours. The catalyst was removed by filtration (celite) and washed with ethanol (about 20 mL). The filtrate was concentrated to dryness under reduced pressure to give a yellow oil, which was dissolved in MeOH (3 mL) and purified by preparative HPLC (method B). The residue was dissolved in acetonitrile (2 mL) and water (2 mL) and lyophilized to give the title compound as a pale yellow solid (85mg, 57%).

Method C LC-MS (electrospray): m/z =420.5 (M + H) ⁺ RT =3.17 min

Example 134: (cyclobutylmethyl) ({ 6- [ (4- { 1H-pyrrolo [2,3-b ] pyridin-5-yl } -1H-imidazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine

Step 1:1- (p-toluenesulfonyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine

The reaction solution of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b]Pyridine (500mg, 2.05mmol), DIPEA (714. Mu.l, 4.10 mmol), DMAP (25mg, 0.20mmol) and TsCl (469mg, 2.45mmol) were combined in DCM (10 mL), and the mixture was stirred at room temperature for 20 hours. The mixture is washed with NaHCO ₃ (saturation, 20 mL) quench and separate the phases. The aqueous phase was extracted with DCM (2X 20 mL) and the combined organic layers were washed with Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Purification by upper chromatography (eluting with 0% to 100% etoac/heptane) to give the title compound as a white solid (320mg, 37%).

Method B LC-MS (electrospray): m/z =399.2 (M + H) ⁺ RT =1.65 min

Step 2:5- (1H-imidazol-4-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine

1- (p-toluenesulfonyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo [2,3-b]Pyridine (320mg, 0.76mmol), 4-bromoimidazole-1-carboxylic acid tert-butyl ester intermediate 20 (226mg, 0.92mmol) and K ₂ CO ₃ (1.2M aqueous, 1.91mL, 2.29mmol) were combined in 1,4-dioxane (5 mL) and the mixture was bubbled with nitrogen for 5 minutes. Addition of PdCl ₂ (dppf) (56mg, 0.08mmol), the mixture was bubbled further briefly and the container was sealed. The mixture was heated at 100 ℃ for 2 hours. Additional tert-butyl 4-bromoimidazole-1-carboxylate (120mg, 0.49mmol) was added and heating continued for 3 hours. The mixture was cooled to room temperature and NaHCO was used ₃ (saturated, 30 mL) and extracted with DCM (2 × 30 mL) and chloroform/isopropanol (3. The combined organic extracts are passed over Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Purification by chromatography (kp-NH, 0% to 100% EtOAc/heptane followed by 0% to 20% meoh/EtOAc elution) to give the title compound as a pale orange solid (163mg, 57%).

Method B LC-MS (electrospray): m/z =339.2 (M + H) ⁺ RT =1.44 min

And step 3:2- [ [ tert-Butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- [1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-5-yl ] imidazol-1-yl ] methyl ] indole-1-carboxylic acid tert-butyl ester

Reacting 5- (1H-imidazol-4-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b]Pyridine (162mg, 0.48mmol), 6- (bromomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino group]Methyl radical]Indole-1-carboxylic acid tert-butyl ester intermediate 19 (410mg, 0.81mmol), K ₂ CO ₃ (199mg, 1.4 mmol) and sodium iodide (7 mg, 0.05mmol) were combined in DMF (8 mL) and the mixture was heated at 80 ℃ for 6 hours. The mixture was cooled to room temperature and diluted with EtOAc (50 mL) and brine (50 mL). The phases were separated and the organic phase was washed with brine (4X 50 mL). Subjecting the organic layer to Na ₂ SO ₄ Dried and evaporated under vacuum. Passing the residue through SiO ₂ Purification by chromatography on (0% to 100% EtOAc/heptane followed by 0% to 20% meoh/EtOAc elution) to give the title compound as a light yellow solid (128mg, 26%).

Method M LC-MS (electrospray): m/z =765.35 (M + H) ⁺ RT =1.79 min

And 4, step 4: (cyclobutylmethyl) ({ 6- [ (4- { 1H-pyrrolo [2,3-b ] pyridin-5-yl } -1H-imidazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine

Tert-butyl 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- [1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-5-yl ] imidazol-1-yl ] methyl ] indole-1-carboxylate (120mg, 0.16mmol) was dissolved in MeOH (5 mL) and NaOMe (90mg, 1.67mmol) was added. The vessel was sealed and the mixture was heated at 90 ℃ for 2 hours. The mixture was cooled to room temperature and HCl (4M in dioxane, 5 mL) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was evaporated under vacuum. The residue was dissolved in MeOH and purified by ion exchange (SCX-2, washed with MeOH and eluted with ammonia in MeOH). The basic eluent was evaporated under vacuum. The residue was purified by preparative HPLC (method B) to give the title compound as a pale yellow solid (27mg, 42%).

Method D LC-MS (electrospray): m/z =411.2 (M + H) ⁺ RT =4.03 min

Example 135: (cyclobutylmethyl) ({ 6- [ (4- { imidazo [1,5-a ] pyridin-8-yl } -1H-1,2,3-triazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine

The title compound was prepared in a similar manner to example 63 using intermediates 7 and 14 to give (192mg, 74%) as a pale yellow solid.

The method C comprises the following steps: LC-MS (electrospray): m/z =412.4 (M + H) ⁺ RT =3.13 min

Example 136: n- [ (2- { [ (2,2-dimethylpropyl) amino ] methyl } -1H-indol-6-yl) methyl ] -1H-pyrrolo [2,3-b ] pyridine-5-carboxamide

The title compound was prepared from intermediate 21 using the procedure described in example 2, step 5, to give as an off-white solid (30mg, 23%).

The method C comprises the following steps: LC-MS (electrospray): m/z =390.4 (M + H) ⁺ RT =3.16 min

Example 137: n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -1H-pyrrolo [2,3-b ] pyridine-5-carboxamide

The title compound was prepared in the same manner as in example 136 to give (83mg, 43%) as a white solid.

The method C comprises the following steps: LC-MS (electrospray): m/z =388.4 (M + H) ⁺ RT =2.95 min

Example 138: (cyclobutylmethyl) ({ 6- [ (4- { 1H-pyrrolo [2,3-b ] pyridin-5-yl } -1H-1,2,3-triazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine

Step 1:2- [ [ tert-Butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- (1H-pyrrolo [2,3-b ] pyridin-5-yl) triazol-1-yl ] methyl ] indole-1-carboxylic acid tert-butyl ester

Under nitrogen atmosphere, 1H-pyrrolo [2,3-b]Pyridine-5-carboxaldehyde (60mg, 0.411mmol) was suspended in MeOH (anhydrous, 1 mL) and THF (anhydrous, 1 mL), dimethyl (1-diazo-2-oxopropyl) phosphonate (0.12mL, 0.821mmol) and potassium carbonate (170mg, 1.23mmol) were added, and the mixture was stirred at room temperature for 3 hours. Addition of 6- (azidomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino group]Methyl radical]Indole-1-carboxylic acid tert-butyl ester intermediate 7 (193mg, 0.411mmol) and copper iodide (1) (1695g, 0.0821mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with DCM using a Telos phase separator. The organics were evaporated to dryness and passed through SiO ₂ Purification by upper chromatography (eluting with 0% to 60% etoac in heptane) to provide the title compound as a white solid (90mg, 36%).

The method B comprises the following steps: LC-MS (electrospray): m/z =612.4 (M + H) +, RT =2.15 min

Step 2: (cyclobutylmethyl) ({ 6- [ (4- { 1H-pyrrolo [2,3-b ] pyridin-5-yl } -1H-1,2,3-triazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine

HCl in dioxane (4M in dioxane, 1 mL) was added to a solution of tert-butyl 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- (1H-pyrrolo [2,3-b ] pyridin-5-yl) triazol-1-yl ] methyl ] indole-1-carboxylate (60mg, 0.09mmol) in MeOH (1 mL) and the mixture was stirred at 60 ℃ for 3 hours. The mixture was evaporated to dryness and purified by preparative HPLC (method B) to give the title compound as a white solid (19mg, 44%).

The method C comprises the following steps: LC-MS (electrospray): m/z =412.4 (M + H) ⁺ RT =3.18 min

Intermediate 22: 8-Bromoimidazo [1,5-a ] pyridines

A mixture of formaldehyde (37%, 16mL, 0.22mol) and ammonium acetate (20.7g, 0.27mol) in acetic acid (100 mL) was stirred at room temperature for 10 minutes, followed by the addition of 3-bromopyridine-2-carbaldehyde (5.0g, 26.9 mmol) in portions over 2 hours, and the mixture was stirred at room temperature for 3 hours.

Intermediate 23: 8-ethynylimidazo [1,5-a ] pyridine

The title compound was prepared from intermediate 22 using the procedure described in example 63, steps 5 and 6 to yield (1.29g, 84%) as a brown solid.

The method C comprises the following steps: LC-MS (electrospray): m/z =285.2 (2M + H) +, RT =2.01 min

Example 140: n- [ (3-fluoro-1-bicyclo [1.1.1] pentyl) methyl ] -1- [6- [ (4-imidazo [1,5-a ] pyridin-8-yltriazol-1-yl) methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methylamine

Step 1: 2-bromo-5-iodopyridin-4-amines

To a stirred solution of 2-bromopyridin-4-amine (25g, 144.5 mmol) in acetonitrile (500 mL) was added N-iodosuccinimide (39.01g, 173.4 mmol). The resulting reaction mixture was stirred at 80 ℃ for 16 hours. The reaction was repeated in the same manner and combined and used for the work-up. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in saturated sodium thiosulfate solution (700 mL) and extracted with ethyl acetate (250 mL. Times.3). The combined organic layers were passed over anhydrous Na ₂ SO ₄ Dried and concentrated under vacuum. Passing the crude product through SiO ₂ Purification by upper chromatography (eluting with 5% ethyl acetate in hexanes) gave the title compound as a yellow solid (37g, 80%).

¹ H NMR (400MHz, DMSO-d 6) delta 8.16 (s, 1H), 6.77 (s, 1H), 6.50 (bs, 2H). LCMS:3.709 min

Step 2: 2-bromo-5- (3,3-diethoxyprop-1-yn-1-yl) pyridin-4-amine

To a stirred solution of 2-bromo-5-iodopyridin-4-amine (18.5g, 62.0 mmol) in THF (185 mL) was added triethylamine (152.6 mL,1086.4 mmol), triphenylphosphine (0.32g, 1.2mmol) and PdCl at room temperature ₂ (PPh ₃ ) ₂ (0.43g, 0.62mmol). The solution was dissolved by bubbling nitrogen into the solution for 0.5 hourThe liquid is degassed. Copper (I) iodide (0.23g, 1.2 mmol) and 3,3-diethoxyprop-1-yne (11.9 g, 93.1mmol) were then added and the reaction was stirred at 60 ℃ for 16 h. The reaction was repeated in the same manner and combined and used for the work-up. The reaction was cooled to room temperature and poured into saturated sodium bicarbonate (700 mL). The aqueous layer was extracted with ethyl acetate (250 mL. Times.3). The combined organic layers were passed over anhydrous Na ₂ SO ₄ Dried and concentrated under vacuum. Passing the crude product through SiO ₂ Purification by upper chromatography (eluting with 12% ethyl acetate in hexanes) gave the title compound (33.5 g) as a brown solid.

¹ H NMR：(400MHz，CDCl ₃ )δ8.14(s，1H)，6.78(s，1H)，5.52(s，1H)，4.82(bs，2H)，3.85-3.77(m，2H)，3.71-3.64(m，2H)，1.29(t，J＝6.8Hz，6H)。

And step 3:2- (Dimethoxymethyl) -1H-pyrrolo [3,2-c ] pyridine-6-carbaldehyde

To a solution of 2-bromo-5- (3,3-diethoxyprop-1-yn-1-yl) pyridin-4-amine (16.5g, 5.53mmol) in NMP (165 mL) was added potassium tert-butoxide (12.42g, 110.7 mmol). The reaction mixture was allowed to stir at 50 ℃ for 3 hours. The reaction was repeated in the same manner and combined and used for the work-up. The reaction was cooled to room temperature and poured into cold water (500 mL). The aqueous layer was extracted with diethyl ether (250 mL. Times.3). The combined organic layers were passed over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo to give the title compound (35.0 g) as a yellow liquid.

¹ H NMR：(400MHz，CDCl ₃ )δ8.78(bs，1H)，8.66(s，1H)，7.50(s，1H)，6.60(s，1H)，5.74(s，1H)，3.73-3.58(m，4H)，1.28(t，J＝7.2Hz，6H)。

Sodium hydride (60%, 590mg,14.8 mmol) was added to 6-bromo-2- (dimethoxymethyl) -1H-pyrrolo [3,2-c]An ice-cooled solution of pyridine (1000mg, 3.69mmol) in anhydrous THF (32.5 mL) and the mixture was stirred under ice-cooling for 10 minutes. The mixture was cooled to-78 ℃ and t-BuLi (1.9M in pentane, 10mL,18.4 mmol) was added, and the mixture was stirred at-78 ℃ for 1 hour. Anhydrous DMF (1714 μ L,22.1 mmol) was added and the mixture was stirred at-78 ℃ for 45 min. The mixture was then saturated with NH ₄ Cl (sat, 30 mL) was quenched and extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (2X 40 mL) over MgSO ₄ Dried and concentrated under reduced pressure. Passing the residue through SiO ₂ Purification by upper chromatography (eluting with 20% to 100% etoac in heptane) to give as a white solid (650 mg, 78%).

The method C comprises the following steps: LC-MS (electrospray): m/z =221.1 (M + H) +, RT =1.84 min

And 4, step 4:2- (Dimethoxymethyl) -6-formyl-pyrrolo [3,2-c ] pyridine-1-carboxylic acid tert-butyl ester

Boc anhydride (750mg, 3.44mmol) was added to 2- (dimethoxymethyl) -1H-pyrrolo [3,2-c]A solution of pyridine-6-carbaldehyde (650mg, 2.86mmol) and DMAP (70mg, 0.573mmol) in acetonitrile (21 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness in NaHCO ₃ (saturated, 10 mL)/water (20 mL) and extracted with DCM (3X 20 mL) using a Telos phase separator. The organics were evaporated to dryness and passed through SiO ₂ Purification by upper chromatography (eluting with 0% to 60% etoac in heptane) to give (790 mg, 77%) as a colourless oil which solidified to a white solid on scraping.

The method A comprises the following steps: LC-MS (electrospray): m/z =321.0 (M + H) +, RT =1.14 min

And 5:2- (Dimethoxymethyl) -6- (hydroxymethyl) pyrrolo [3,2-c ] pyridine-1-carboxylic acid tert-butyl ester

Reacting NaBH ₄ (71mg, 1.87mmol) was added to 2- (dimethoxymethyl) -6-formyl-pyrrolo [3,2-c ]An ice-cold solution of pyridine-1-carboxylic acid tert-butyl ester (500mg, 1.56mmol) in MeOH (16 mL) and the mixture stirred for 15 min. The mixture was quenched with water (5 mL) and extracted with DCM (3X 10 mL) using a Telos phase separator. The organic phase was evaporated to dryness to give the title compound as a colorless oil (380mg, 73%) which solidified to a white solid upon scraping.

The method A comprises the following steps: LC-MS (electrospray): m/z =323.0 (M + H) +, RT =0.87 min

Step 6:6- (Azidomethyl) -2- (Dimethoxymethyl) pyrrolo [3,2-c ] pyridine-1-carboxylic acid tert-butyl ester

At 0 ℃ under N ₂ Down direction 2- (Dimethoxymethyl) -6- (hydroxymethyl) pyrrolo [3,2-c]To a stirred solution of pyridine-1-carboxylic acid tert-butyl ester (390mg, 1.14mmol) and DBU (339. Mu.L, 2.27 mmol) in anhydrous DMF (6.7 mL) was added DPPA (489. Mu.L, 2.27 mmol) dropwise and the mixture was stirred at room temperature for 72 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (5X 10 mL). The organics were washed with brine (10 mL) and dried (MgSO) ₄ ) And concentrated to a pink oil. Passing the crude product through SiO ₂ Chromatographed (eluted with 0% to 100% etoac in heptane) to give the title compound as a colorless oil (394mg, 99%).

Method J: LC-MS (electrospray): m/z =348.4 (M + H) +, RT =0.88 min

And 7:6- (azidomethyl) -1H-pyrrolo [3,2-c ] pyridine-2-carbaldehyde

Reacting 6- (azidomethyl) -2- (dimethoxymethyl) pyrrolo [3,2-c]a solution of pyridine-1-carboxylic acid tert-butyl ester (100mg, 0.29mmol) in THF (2 mL), water (2 mL) was stirred at room temperature. Acetic acid (2 mL) was added and stirring was continued for another 2 hours. The mixture was then stirred at 50 ℃ for 16 hours. The reaction was concentrated vigorously and the residue was taken up with NaHCO ₃ (saturated, 15 mL) diluted and treated with IPA: CHCl ₃ (1. The organics were dried (MgSO) ₄ ) And concentrated to give the title compound (94 mg, quantitative) as an off-white solid.

Method J: LC-MS (electrospray): m/z =204.2 (M + H) +, RT =0.63 min

And 8:1- [6- (azidomethyl) -1H-pyrrolo [3,2-c ] pyridin-2-yl ] -N- [ (3-fluoro-1-bicyclo [1.1.1] pentyl) methyl ] methylamine

Will { 3-fluoro bicyclo [1.1.1]Pentane-1-yl } methylamine hydrochloride (65mg, 0.43mmol), 6- (azidomethyl) -1H-pyrrolo [3,2-c]Solutions of pyridine-2-carbaldehyde (94mg, 0.29mmol), STAB (362mg, 1.71mmol), and N-ethyl-N-isopropyl-propan-2-amine (0.15mL, 0.86mmol) in DCE (6 mL) in N ₂ The mixture was stirred at 60 ℃ for 2 hours. The mixture is washed with NaHCO ₃ (saturated, 15 mL) diluted and treated with IPA: CHCl ₃ (1. The organics were dried (MgSO) ₄ ) And concentrated to a yellow oil (0.3 g). Passing the crude product through SiO ₂ Purification by upper chromatography (15% to 100% EtOAc in heptane, followed by elution with 0% to 12% meoh in EtOAc) to give the title compound as a colorless oil (81mg, 71%).

Method J: LC-MS (electrospray): m/z =301.3 (M + H) +, RT =0.63 min

And step 9: n- [ (3-fluoro-1-bicyclo [1.1.1] pentyl) methyl ] -1- [6- [ (4-imidazo [1,5-a ] pyridin-8-yltriazol-1-yl) methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methylamine

1- [6- (azidomethyl) -1H-pyrrolo [3,2-c)]Pyridin-2-yl]-N- [ (3-fluoro-1-bicyclo [ 1.1.1)]Pentyl) methyl group]Methylamine (81mg, 0.202mmol) and 8-ethynylimidazo [1,5-a]A solution of pyridine intermediate 23 (29mg, 0.202mmol) in DMF (1.7 mL) and water (0.6 mL) was treated with sodium ascorbate (44mg, 0.223mmol) and CuSO at room temperature ₄ (7mg, 0.041mmol) and stirred at room temperature for 1 hour. The mixture was concentrated and purified by preparative HPLC (method B). The product containing fractions were lightly concentrated to remove MeCN and the remaining aqueous solution was diluted with IPA, CHCl ₃ (1. The organics were dried (MgSO) ₄ ) And concentrated to a residue which was purified by acidic reverse phase chromatography (Biotage Isolera Four;6gSfar Duo C18-D; 10% to 100% mecn (0.1% formic acid)) in water (0.1% formic acid). The product fraction was taken up in NaHCO ₃ (saturated, 5 mL) basified and concentrated to remove MeCN, remaining aqueous solution was made up with IPA: CHCl ₃ (1. The organics were dried (MgSO) ₄ ) And concentrated to give the title compound as an off-white solid (11mg, 12%).

The method C comprises the following steps: LC-MS (electrospray): m/z =443.4 (M + H) +, RT =2.49 min

Intermediate 25: 4-azido-1-, (

Alk-2-yl) -1H-indazoles

Step 1: 1H-indazol-4-amines

To a solution of 4-nitro-1H-indazole (50.0 g, 153.33mmol) in MeOH (500 mL) at room temperature was added Pd/C (50% wet) (10%, 5.00 g). The reaction mixture was placed under a hydrogen atmosphere and stirred at room temperature for 5 hours. The reaction mixture was filtered through a pad of celite and washed with additional MeOH (3 × 200 mL). The combined filtrates were concentrated in vacuo to give the title compound (14.0 g, 34%).

Method G: LC-MS (electrospray): m/z =134.0 (M + H) ⁺ RT =0.49 min

Step 2: 4-azido-1H-indazoles

To a solution of 1H-indazol-4-amine (0.50g, 3.14mmol) in acetonitrile (5 mL) at 0 deg.C was added tert-butyl nitrite (1.16g, 12.57mmol) followed by sodium azide (0.97g, 15.7mmol). The resulting reaction mixture was stirred at 60 ℃ for 16 hours. The reaction mixture was cooled to room temperature. This procedure was repeated five times and the combined reaction was poured into water (250 mL). The mixture was extracted with ethyl acetate (3X 100 mL). The combined organic layers were dried (Na) ₂ SO ₄ ) And concentrated under vacuum. Passing the crude material through SiO ₂ (60 to 120) the column was purified by elution with 15% EtOAc in hexane to give the title compound (0.90g, 25%). LCMS:1.504 min, MS: ES +160.1 (M + 1);

method G: LC-MS (electrospray): m/z =160.1 (M + H) ⁺ RT =1.50 min

And step 3: 4-azido-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

To a solution of 4-azido-1H-indazole (1.0 g,6.3 mmol) in EtOAc (10 mL) at 0 deg.C was added dihydropyran (1.30g, 15.5 mmol) followed by TFA (0.07g, 0.63mmol) and the resulting reaction mixture was stirred at 70 deg.C for 4 hours. The reaction mixture was allowed to cool to room temperature and saturated NaHCO was poured in ₃ (saturated, 100 mL) and extracted with ethyl acetate (2X 50 mL). The organic layer was dried (Na) ₂ SO ₄ ) And concentrated under vacuum. Passing the crude material through SiO ₂ (60 to 120) coloringThe spectrum was purified with 8% etoac in hexanes elution to give the title compound (0.9g, 59%).

Method G: LC-MS (electrospray): m/z =244.1 (M + H) ⁺ RT =2.07 min

Intermediate 26:2- (((tert-Butoxycarbonyl) (cyclobutylmethyl) amino) methyl) -6- (prop-2-yn-1-yl) -1H-indole-1-carboxylic acid tert-butyl ester

Step 1:1- (6-bromo-1H-indol-2-yl) -N- (cyclobutylmethyl) methylamine

To a stirred solution of 6-bromo-1H-indole-2-carbaldehyde (4.00g, 17.80mmol) and cyclobutylmethylamine (3.04g, 35.70mmol) in DCE/MeOH (200mL, 4: 1) at 0 deg.C was added sodium triacetoxyborohydride (11.32g, 53.40mmol) in portions. The resulting solution was then stirred at room temperature for 16 hours. The reaction was repeated in the same manner and combined and used for the work-up. The reaction was poured into water (100 mL), and the aqueous layer was extracted with dichloromethane (70 mL. Times.3). The combined organic layers were passed over anhydrous Na ₂ SO ₄ Dried and concentrated under vacuum. Passing the crude product through SiO ₂ Purification by chromatography (eluting with 2.2% meoh in DCM) to give the title compound (7.0 g).

¹ H-NMR(400MHz，DMSO-d ₆ )δ11.12(s，1H)，7.49(s，1H)，7.39(d，J＝8.4Hz，1H)，7.05(dd，J＝8.4，2.0Hz，1H)，6.28(s，1H)，3.79(s，2H)，2.45-2.37(m，1H)，2.02-1.94(m，2H)，1.91(s，2H)，1.86-1.75(m，2H)，1.68-1.58(m，2H)。

And 2, step: 6-bromo-2- (((tert-butoxycarbonyl) (cyclobutylmethyl) amino) methyl) -1H-indole-1-carboxylic acid tert-butyl ester

To a stirred solution of 1- (6-bromo-1H-indol-2-yl) -N- (cyclobutylmethyl) methylamine (4.00g, 13.60mmol) in THF (50 mL) was added LiHMDS (1M in THF, 41.00ml, 41.00mmol) at room temperature followed by Boc anhydride (11.87g, 54.40mmol). The mixture was heated at 70 ℃ for 16 h, cooled to room temperature and poured into water (100 mL). The aqueous layer was extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were passed over anhydrous Na ₂ SO ₄ Dried and concentrated under vacuum. Passing the crude product through SiO ₂ Purification by upper chromatography (eluting with 8% ethyl acetate in hexanes) gave the title compound (5.0 g, 30%).

Method LC04_ ABF3: LC-MS (electrospray): m/z =493.6/495.6 (M + H) ⁺ RT =2.81 minutes

MS(ESI-MS)：C ₂₄ H ₃₃ BrN ₂ O ₄ [MH]M/z of + is calculated 492.16, found 493.63 and 495.63, [ M +1 and M +3 ]]。

And 3, step 3:2- (((tert-Butoxycarbonylmethyl) (cyclobutylmethyl) amino) methyl) -6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 6-bromo-2- (((tert-butoxycarbonyl) (cyclobutylmethyl) amino) methyl) -1H-indole-1-carboxylate (5.00g, 10.16mmol) in 1,4-dioxane (50 mL) was added potassium acetate (3.00g, 30.40mmol) and bis pinacoldiborane (10.32g, 40.60mmol). The solution was degassed by bubbling nitrogen into the solution for 0.5 h, and PdCl was added at room temperature ₂ (dppf) (0.740 g, 1.01mmol). The resulting reaction mixture was heated at 90 ℃ for 2 hours, cooled to room temperature and poured into water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were passed over anhydrous Na ₂ SO ₄ Dried and concentrated under vacuum. Passing the crude product through SiO ₂ Purifying by upper chromatography (eluting with 10% ethyl acetate in hexane) The title compound (5.0 g, 92%) was obtained.

Method LC04-ABR2: LC-MS (electrospray): m/z =542.18 (M + H) ⁺ RT =3.42 min

MS(ESI-MS)：C ₃₀ H ₄₅ BN ₂ O ₆ [MH]The calculated value of m/z of + is 540.34, found 542.18[ M +1 ]]。

And 4, step 4:2- (((tert-Butoxycarbonyl) (cyclobutylmethyl) amino) methyl) -6- (3- (trimethylsilyl) prop-2-yn-1-yl) -1H-indole-1-carboxylic acid tert-butyl ester

To a stirred mixture of tert-butyl 2- (((tert-butoxycarbonyl) (cyclobutylmethyl) amino) methyl) -6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole-1-carboxylate (5.00g, 9.25mmol) in 1,4-dioxane (50 mL) and water (2.5 mL) was added potassium carbonate (3.84g, 27.70mmol) and 3-bromo-1- (trimethylsilyl) -1-propyne (5.30g, 27.70mmol). The solution was degassed by bubbling nitrogen into the solution for 0.5 h, and PdCl was added at room temperature ₂ (dppr) (0.680 g, 0.92mmol). The reaction was heated at 80 ℃ for 5 hours, cooled to room temperature and poured into water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were passed over anhydrous Na ₂ SO ₄ Dried, filtered and concentrated under vacuum. Passing the crude product through SiO ₂ Purification by column chromatography (eluting with 60% ethyl acetate in hexanes) gave the title compound (1.2g, 24%).

1H NMR：(400MHz，dmso-d ₆ )8.10(s，1H)，7.49(d，J＝8.4Hz，1H)，7.13(d，J＝8.0Hz，1H)，6.26(s，1H)，4.66(s，2H)，3.81(s，2H)，1.99-1.90(m，2H)，1.82-1.76(m，2H)，1.70-1.66(m，10H)，1.47(s，9H)，0.16(s，9H)。

And 5:2- (((tert-Butoxycarbonyl) (cyclobutylmethyl) amino) methyl) -6- (prop-2-yn-1-yl) -1H-indole-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 2- (((tert-butoxycarbonyl) (cyclobutylmethyl) amino) methyl) -6- (3- (trimethylsilyl) prop-2-yn-1-yl) -1H-indole-1-carboxylate (3.00g, 5.70mmol) in THF (20 mL) at 0 ℃ was added TBAF (1M in THF, 5.70ml, 5.70mmol). The reaction was stirred at 0 ℃ for 30 minutes. Then poured into water (30 mL) and extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were passed over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo to afford the title compound (1.5g, 57%).

Method LC03_ ABR2: LC-MS (electrospray): m/z =493.6/495.6 (M + H) ⁺ RT =3.27 min

MS(ESI-MS)：C ₂₇ H ₃₆ N ₂ O ₄ [MH]The calculated value of m/z of + is 452.27, found 453.91M +1]. (LCMS: 90.21%, room temperature: 3.27 min).

Intermediate 27:2- (tert-Butoxycarbonyl) ((3,3-difluorocyclobutyl) methyl) amino) methyl) -6- (prop-2-yn-1-yl) -1H-indole-1-carboxylic acid tert-butyl ester

The title compound was prepared from 1- (3,3-difluorocyclobutyl) methylamine in the same manner as intermediate 26 to give the title compound (0.36g, 69%).

¹ H NMR：(DMSO-d ₆ ，400MHz)δ8.10(s，1H)，7.48(d，J＝7.6Hz，1H)，7.13(d，J＝7.6Hz，1H)，6.26(s，1H)，4.69(br s，2H)，3.75(br s，2H)，3.43(d，J＝6.4Hz，3H)，3.12(d，J＝2.0Hz，1H)，2.66-2.32(m，4H)，1.65(s，9H)1.44(s，9H)

Intermediate 28:

step 1: (2-Chloropyridin-3-yl) carbamic acid tert-butyl ester

To a stirred solution of 2-chloropyridin-3-amine (10.00g, 78.00mmol) in DCM (50 mL) was added Et at room temperature ₃ N (23.7mL, 234.0mmol), boc anhydride (25.5g, 117.0mmol) and DMAP (0.95g, 7.8mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 mL), and the aqueous layer was extracted with dichloromethane (100 mL. Times.3). The combined organic layers were passed over anhydrous Na ₂ SO ₄ Dried and concentrated under vacuum. Passing the crude product through SiO ₂ Purification by chromatography (eluting with 11% ethyl acetate in hexanes) gave the title compound (8.5g, 47%).

MS(ESI-MS)：C ₁₀ H ₁₃ ClN ₂ O ₂ [MH]+ M/z calculated 228.07, found 229.1 and 231.1, [ M +1 ] and M +3]。

And 2, step: (2-cyanopyridin-3-yl) carbamic acid tert-butyl ester

To a solution of tert-butyl (2-chloropyridin-3-yl) carbamate (8.50g, 37.10 mmol) in DMF (50 mL) were added zinc dust (0.29g, 4.40mmol) and zinc cyanide (2.61g, 22.20 mmol). The solution was degassed by bubbling nitrogen into the solution for 0.5 h, followed by addition of PdCl ₂ (dppf) (0.54g, 0.74mmol) and Pd ₂ (dba) ₃ (0.34g, 0.37mmol). The resulting reaction mixture was stirred at 90 ℃ for 8 hours. The reaction was then poured into ice-cold water (500 mL). The aqueous layer was extracted with ethyl acetate (100 mL. Times.3). The combined organic layers were passed over anhydrous Na ₂ SO ₄ Dried and concentrated under vacuum. Passing the crude product through SiO ₂ Purification by chromatography (eluting with 15% ethyl acetate in hexanes) gave the title compound (4.5g, 55%).

¹ H-NMR(400MHz，DMSO-d ₆ )δ9.72(s，1H)，8.49(dd，J＝4.4，1.2Hz，1H)，7.97(dd，J＝8.4，1.2Hz，1H)，7.70(dd，J＝8.4，44Hz，1H)，1.49(s，9H)。

And step 3: (2- (aminomethyl) pyridin-3-yl) carbamic acid tert-butyl ester

To a stirred solution of 1- (tert-butyl (2-cyanopyridin-3-yl) carbamate (3.80g, 17.30mmol) in ethyl acetate (100 mL) was added raney nickel (0.76ml, 20%). The reaction was stirred under hydrogen (40 bar) at room temperature for 6 h, then the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (4.3 g).

MS(ESI-MS)：C ₁₁ H ₁₇ N ₃ O ₂ [MH]The calculated value of m/z of + is 223.13, found 224.52M +1]。

And 4, step 4: (2- (carboxamidomethyl) pyridin-3-yl) carbamic acid tert-butyl ester

Tert-butyl (2- (aminomethyl) pyridin-3-yl) carbamate (4.30g, 19.20 mmol) in ethyl formate (100 mL) was heated at 65 ℃ for 16 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. Passing the crude product through SiO ₂ Purification by chromatography (eluting with 2.5% meoh in DCM) to give the title compound (2.80g, 11.14mmol).

¹ H-NMR(400MHz，DMSO-d ₆ )δ9.13(s，1H)，8.65(s，1H)，8.29(dd，J＝4.8，1.6Hz，1H)，8.10(d，J＝1.6Hz，1H)，7.87(dd，J＝76Hz，1H)，7.31(q，J＝8.0Hz，4.4Hz，1H)，4.38(d，J＝6.0Hz，2H)，1.47(s，9H)。

And 5: imidazo [1,5-a ] pyridin-8-ylcarbamic acid tert-butyl ester

To a stirred solution of tert-butyl (2- (formamidomethyl) pyridin-3-yl) carbamate (2.80g, 11.10mmol) in DCM (50 mL) was added TEA (4.7mL, 33.3mmol) at room temperature. Followed by dropwise addition of POCl at 0 deg.C ₃ . The resulting reaction mixture was allowed to stir at 0 ℃ for 1 hour, followed by pouring NaHCO ₃ (saturated, 50 mL). The aqueous layer was extracted with dichloromethane (250 mL. Times.2). The combined organic layers were passed over anhydrous Na ₂ SO ₄ Dried and concentrated under vacuum to give the title compound (3.5g, 57%).

Step 6: imidazo [1,5-a ] pyridin-8-amine hydrochloride

To a stirred solution of imidazo [1,5-a ] pyridin-8-ylcarbamic acid tert-butyl ester (3.50g, 15.00mmol) in DCM (30 mL) was added HCl (4M in dioxane, 35 mL) at room temperature. The resulting reaction mixture was allowed to stir at room temperature for 2 hours. The solution was then concentrated under vacuum to give the title compound (4.00 g).

¹ H-NMR(400MHz，DMSO-d ₆ )δ10.65(s，1H)，9.58(s，1H)，8.25(s，1H)，7.88(d，J＝6.8Hz，1H)，6.92(t，J＝7.2Hz，1H)，6.11(d，J＝7.6Hz，1H)。

And 7: 8-Azidoimidazo [1,5-a ] pyridine

Imidazo [1,5-a at 0 DEG C]A stirred solution of pyridin-8-amine hydrochloride (0.50g, 3.70mmol) in acetonitrile (10 mL) was added tert-butyl nitrite (1.2 g, 11.2mmol) and stirring was continued at 0 ℃ for 5 minutes. Addition of NaN at 0 deg.C ₃ (0.96g, 14.8 mmol) in water (0.5 mL). The reaction was then stirred at O ℃ for 1 hour. In the same way toThe reactions were repeated, combined and poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (30 mL. Times.2). The combined organic layers were passed over Na ₂ SO ₄ Dried and concentrated under vacuum to give the title compound (0.05g, 10%).

¹ H-NMR(400MHz，DMSO-d ₆ )δ8.46(s，1H)，8.21-8.19(m，1H)，7.38(s，1H)，6.71-6.65(m，2H)。

Intermediate 29: 4-azidoisoquinoline.

To a stirred solution of isoquinolin-4-amine (1.00g, 6.90mmol) in acetic acid (10 mL) was added NaNO in water (3 mL) ₂ (0.96g, 13.80mmol). Added dropwise at 0 ℃, after which the reaction was stirred at 0 ℃ for a further 15 minutes. NaN in water (3 mL) was added dropwise at 0 deg.C ₃ (0.90g, 13.80mmol). The reaction was then stirred at room temperature for 2 hours. Then poured into water (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL. Times.3). Subjecting the organic layer to Na ₂ SO ₄ Dried and concentrated under vacuum. Passing the crude product through SiO ₂ Purification by chromatography (eluting with 20% ethyl acetate in hexane) gave the title compound (0.35g, 30%).

¹ H-NMR(400MHz，DMSO-d ₆ )δ9.16(s，1H)，8.56(s，1H)，8.17(d，J＝8.0Hz，1H)，8.01(d，J＝8.0Hz，1H)，7.85(td，J＝6.8，1.2Hz，1H)，7.77(td，J＝8.0，0.8Hz，1H)。

Example 141: (cyclobutylmethyl) [ (6- { [1- (1H-indazol-4-yl) -1H-1,2,3-triazol-4-yl ] methyl } -1H-indol-2-yl) methyl ] amine

Step 1:2- ({ [ (tert-butoxy) carbonyl](cyclobutylmethyl) amino } methyl) -6- ({ 1- [1-, (

Alk-2-yl) -1H-indazol-4-yl]-1H-1,2,3-triazol-4-yl } methyl) -1H-indole-1-carboxylic acid tert-butyl ester

Tert-butyl 2- (((tert-butoxycarbonyl) (cyclobutylmethyl) amino) methyl) -6- (prop-2-yn-1-yl) -1H-indole-1-carboxylate intermediate 26 (0.200g, 0.440mmol), 4-azido-1-, (

Alk-2-yl) -1H-indazole intermediate 25 (0.107g, 0.440mmol), sodium ascorbate (0.035g, 0.176mmol), and CuSO ₄ (0.028g, 0.176mmol) in tert-butanol: the mixture in water (1,2ml) was heated at 70 ℃ for 1 hour. The reaction was cooled to room temperature and poured into water (150 mL). The aqueous layer was extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were passed over Na ₂ SO ₄ Dried and concentrated under vacuum. Passing the crude product through SiO ₂ Purification by chromatography (eluting with 34% ethyl acetate in hexanes) gave the title compound (0.150g, 48%).

Method G: LC-MS (electrospray): m/z =696.8 (M + H) ⁺ RT =3.38 min

Step 2: (cyclobutylmethyl) [ (6- { [1- (1H-indazol-4-yl) -1H-1,2,3-triazol-4-yl ] methyl } -1H-indol-2-yl) methyl ] amine

To a stirred solution of 2- (((tert-butoxycarbonyl) (cyclobutylmethyl) amino) methyl) -6- ((1- (1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -1H-1,2,3-triazol-4-yl) methyl) -1H-indole-1-carboxylic acid ester (0.150g, 0.21mmol) in 1,4-dioxane (1.5 mL) was added HCl (4M in dioxane, 5.00 mL) dropwise at room temperature. The resulting mixture was allowed to stir at room temperature for 16 hours. Mixing the mixturePouring Na ₂ CO ₃ The solution (saturated, 100 mL) was taken up and extracted with ethyl acetate (3X 30 mL). The combined organic layers were passed over Na ₂ SO ₄ Dried and concentrated under vacuum. Passing the crude product through SiO ₂ Purification by upper chromatography (eluting with (6% meoh in dichloromethane)) to give the title compound (0.015g, 16%).

Method G: LC-MS (electrospray): m/z =412 (M + H) +, RT =1.34 min

¹ H NMR：(MeOD，400MHz)δ8.46(d，J＝4.4Hz，2H)，7.67(d，J＝8.0Hz，1H)，7.56-7.49(m，3H)，7.40(s，1H)，7.11(d，J＝8.0Hz，1H)，6.61(s，1H)，4.31(d，J＝8.8Hz，4H)，3.08(d，J＝7.6Hz，2H)，2.72-2.66(m，1H)，2.21-2.14(m，2H)，2.04-1.81(m，4H)

The compounds in table 5 were prepared from the appropriate intermediates in a similar manner to example 141.

TABLE 5

Intermediate 30: 3-ethynyl-5-methoxypyridine-2-carbonitrile

The title compound was prepared from 3-bromo-5-methoxy-pyridine-2-carbonitrile (example 63, step 1) using procedures analogous to those described in example 63, steps 5 and 6 to provide the title compound as an off-white solid (564mg, 97%).

The method A comprises the following steps: LC-MS (electrospray): m/z =159.0 (M + H) ⁺ RT =0.98 min

Intermediate 33: 3-ethynyl-5-fluoropyridine-2-carbonitrile

The title compound was prepared from 3-bromo-5-fluoropyridine-2-carbonitrile using procedures analogous to those described in example 63, steps 5 and 6 to provide the title compound as a light brown solid (306mg, 97%).

1H NMR(400MHz，CDCl3)δ8.54(d，J＝2.7Hz，1H)，7.62(dd，J＝7.9，2.7Hz，1H)，3.70(s，1H)。

Intermediate 34: 3-ethynyl-5-methoxypyridine

The title compound was prepared from 3-bromo-5-methoxypyridine using procedures analogous to those described in example 63, steps 5 and 6 to provide the title compound as a brown solid (306mg, 97%).

The method A comprises the following steps: LC-MS (electrospray): m/z =134.0 (M + H) ⁺ RT =0.86 min

Intermediate 31:6- (azidomethyl) -1H-indole-2-carbaldehyde

Step 1: 6-bromo-2- (dimethoxymethyl) -1H-indole

A suspension of 6-bromo-1H-indole-2-carbaldehyde (500mg, 2.23mmol) and trimethoxymethane (3.9mL, 35.7 mmol) in methanol (1.5 mL) was treated with 4-methylbenzenesulfonic acid hydrate (4.2mg, 0.02mmol) and the mixture was stirred at room temperature for 30 minutes, which resulted in the formation of a black solution.

The mixture is washed with NaHCO ₃ (sat, 5 mL) was diluted and extracted with DCM (3X 10 mL). The combined organics were salted with brine(10 mL) washed, dried over magnesium sulfate and concentrated to give a brown oil which was passed through SiO ₂ Purification by upper chromatography (eluting with 0% to 100% etoac in heptane) to give the title compound as an orange oil (570 mg, 91%).

Method J: LC-MS (electrospray): m/z =268.2/270.2 (M + H) ⁺ RT =0.81 min

Step 2:2- (dimethoxymethyl) -1H-indole-6-carbaldehyde

Sodium hydride (60%, 3970 mg, 9.92mmol) was added to an ice-cooled solution of 6-bromo-2- (dimethoxymethyl) -1H-indole (670mg, 2.48mmol) in anhydrous THF (20 mL), and the mixture was stirred under ice-cooling for 10 minutes. The mixture was cooled to-78 ℃ and 2.5M n-BuLi (5.0mL, 12.4 mmol) in hexane was added. The reaction mixture was stirred and allowed to warm slowly to-10 ℃ over 3 hours.

Anhydrous DMF (1.2ml, 14.9 mmol) was added at-10 ℃ and the reaction mixture was stirred and allowed to warm to 0 ℃ over 30 min.

The mixture is then treated with NH ₄ Cl (sat, 30 mL) was quenched and extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (2X 40 mL) and dried (MgSO) ₄ ) And concentrated under reduced pressure. Passing the crude material through SiO ₂ Purification by upper chromatography (elution with 0% to 100% etoac in heptane) to give the title compound as an off-white solid (440mg, 78%).

Method J: LC-MS (electrospray): m/z =220.2 (M + H) ⁺ RT =0.62 min

And step 3:6- (azidomethyl) -1H-indole-2-carbaldehyde

The title compound was prepared from 2- (dimethoxymethyl) -1H-indole-6-carbaldehyde using procedures analogous to those described in example 140, steps 4 to 7 to provide as an off-white solid (155mg, 70%).

Method J: LC-MS (electrospray): m/z =199.4 (M + H) ⁺ RT =0.66 min

Intermediate 32:3- [1- [ (2-formyl-1H-indol-6-yl) methyl ] triazol-4-yl ] -5-methoxy-pyridine-2-carbonitrile

The title compound was prepared from intermediate 31 and intermediate 30 using the procedure described in example 14, step 9, to give (588mg, 78%) as a light brown solid.

The method A comprises the following steps: LC-MS (electrospray): m/z =359.0 (M + H) ⁺ RT =1.07 min

Example 146:3- [1- ({ 2- [ (4,4-dimethyl-1-piperidinyl) methyl ] -1H-indol-6-yl } methyl) -1H-1,2,3-triazol-4-yl ] -5-methoxy-2-pyridinecarbonitrile

3- [1- [ (2-formyl-1H-indol-6-yl) methyl ] triazol-4-yl ] -5-methoxy-pyridine-2-carbonitrile (intermediate 32) (100mg, 0.15mmol), 4,4-dimethylpiperidine hydrochloride (65mg, 0.44mmol) and triethylamine (81. Mu.l, 0.58 mmol) were combined in DCE (3 ml) and the mixture was heated at 70 ℃ for 10 min, followed by the addition of sodium triacetoxyborohydride (154mg, 0.73mmol) (slight gas evolution) and the mixture was heated at 70 ℃ for 3H.

The mixture was cooled to room temperature and NaHCO was used ₃ (aq) (saturated, 20 ml) and extracted with chloroform/isopropanol (3, 1,3 × 30 ml), and the combined organic extracts were dried over sodium sulphate and evaporated in vacuo.

The residue was purified by reverse phase chromatography (30g Sfar c18, with acetonitrile +0.1% nh3/water +0.1% nh3, 10% to 100% elution) to give the title compound as an off-white solid (34mg, 51%).

The method C comprises the following steps: LC-MS (electrospray): m/z =456.4 (M + H) ⁺ RT =4.14 min

TABLE 6

The compounds in table 6 were prepared in the same manner as in example XXX using the appropriate amine.

Example 151:3- {1- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -1H-1,2,3-triazol-4-yl } -5-methoxy-2-pyridinecarbonitrile

The title compound was prepared from intermediate 7 and intermediate 30 using the procedure described in example 141 to give (146mg, 67%) as a white solid.

The method C comprises the following steps: LC-MS (electrospray): m/z =428.5 (M + H) ⁺ RT =3.54 min

Example 152:3- (1- ((2- (((cyclobutylmethyl) amino) methyl) -1H-indol-6-yl) methyl) -1H-1,2,3-triazol-4-yl) -5-fluoromethylpyridinecarbonitrile

The title compound was prepared from intermediate 7 and intermediate 33 using the procedure described in example 141 to give (97mg, 46%) as a white solid.

The method C comprises the following steps: LC-MS (electrospray): m-z＝416.4(M+H) ⁺ RT =3.71 min

Example 153: 1-cyclobutyl-N- ((6- ((4- (5-methoxypyridin-3-yl) -1H-1,2,3-triazol-1-yl) methyl) -1H-indol-2-yl) methyl) methylamine

The title compound was prepared from intermediate 7 and intermediate 34 using the procedure described in example 141 to give as an off-white solid (50mg, 33%).

The method C comprises the following steps: LC-MS (electrospray): m/z =403.4 (M + H) ⁺ RT =3.27 min

Example 154: 5-chloro-3- (1- ((2- (((cyclobutylmethyl) amino) methyl) -1H-indol-6-yl) methyl) -1H-1,2,3-triazol-4-yl) picolinenitrile

Step 1:2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino group]Methyl radical]-6- [ [4- (6-methyl-4,8-dioxo-1,3,6,2-di

Azoloborane-2-yl) triazol-1-yl]Methyl radical]Indole-1-carboxylic acid tert-butyl ester

A mixture of ethynylboronic acid MIDA ester (77mg, 0.426mmol), 6- (azidomethyl) -2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino group]Methyl radical]Indole-1-carboxylic acid tert-butyl ester intermediate 7 (200mg, 0.426mmol) and Cu (OAc) ₂ .H ₂ A mixture of O (8.5mg, 0.04mmol) was diluted with acetonitrile (4 mL) and heated at 60 ℃ for 18 hours.

The blue suspension is evaporated under vacuum (blast shield) and the residue is passed over SiO ₂ Upper chromatography (40% to 100% in heptane-etoac,followed by elution with 10% meoh in EtOAc) to give the title compound as a white foam (204mg, 53%).

Method J: LC-MS (electrospray): m/z =651.6 (M + H) ⁺ RT =0.99 min

Step 2:2- [ [ tert-Butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- (5-chloro-2-cyano-3-pyridinyl) triazol-1-yl ] methyl ] indole-1-carboxylic acid tert-butyl ester

Will contain 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino group]Methyl radical]-6- [ [4- (6-methyl-4,8-dioxo-1,3,6,2-di

Azoboran-2-yl) triazol-1-yl]Methyl radical ]Indole-1-carboxylic acid tert-butyl ester (100mg, 0.111mmol), 3-bromo-5-chloropyridine-2-carbonitrile (30mg, 0.138mmol), K ₂ CO ₃ (107mg，0.78mmol)、Cu(OAc) ₂ .H ₂ Microwave vials of O (11mg, 0.0553mmol) and palladium-Xphos G2 (4.4mg, 5.53. Mu. Mol) were sealed, diluted with MeCN (2 mL) and IPA (0.5 mL) and heated at 120 ℃ for 2X 20 min under microwave irradiation.

The mixture was diluted with DCM and a small amount of water to dissolve a small amount of solid and concentrated in vacuo. The residue was diluted with water and extracted with DCM. The extract was evaporated under vacuum to a brown gum which was passed over SiO ₂ Purification by chromatography (eluting with EtOAc) gave the desired product as a clear gum (contaminated with approximately 20% dechlorinated by-products) (33mg, 47%).

Method J: LC-MS (electrospray): m/z =632.6 (M + H) ⁺ RT =1.19 min

And step 3: 5-chloro-3- (1- ((2- (((cyclobutylmethyl) amino) methyl) -1H-indol-6-yl) methyl) -1H-1,2,3-triazol-4-yl) picolinenitrile

A solution of tert-butyl 2- [ [ tert-butoxycarbonyl (cyclobutylmethyl) amino ] methyl ] -6- [ [4- (5-chloro-2-cyano-3-pyridinyl) triazol-1-yl ] methyl ] indole-1-carboxylate (33mg, 0.05mmol) in MeOH (0.3108 mL) was treated with HCl (4M in dioxane, 0.6 mL) and the resulting mixture was stirred at room temperature for 1 hour. Additional HCl (4M in dioxane, 0.6 mL) was added and the mixture was stirred at room temperature for 36 h.

The reaction mixture was retreated with HCl (4M in dioxane, 0.6 mL) and the mixture was stirred at room temperature for 18 hours.

The pink mixture was evaporated in vacuo and the residue was purified by preparative HPLC (method B) and the product containing fractions were combined, concentrated in vacuo and lyophilized to give the title compound as a white solid (8.6 mg, 38% yield).

The method C comprises the following steps: LC-MS (electrospray): m/z =432.5 (M + H) ⁺ RT =3.78 min

Example 155:2- ((6-azaspiro [3.4] octan-6-yl) methyl) -6- ((4- (imidazo [1,5-a ] pyridin-8-yl) -1H-1,2,3-triazol-1-yl) methyl) -1H-pyrrolo [3,2-c ] pyridine

The title compound was prepared from 6-azaspiro [3.4] octane in a similar manner to example 140 to give the title compound (24mg, 40%) as an off-white solid.

The method C comprises the following steps: LC-MS (electrospray): m/z =439.4 (M + H) ⁺ RT =2.95 min

METTL3/14 methyltransferase assay

Biochemical assay

An enzyme assay was set up to determine the IC50 value for inhibition of RNA methyltransferase activity. The enzyme used was full-length his-tagged METTL3, which was co-expressed with full-length FLAG-tagged METTL14 in a baculovirus expression system. Enzymatic reactions were performed at room temperature in 384-well plates using a medium containing 20mM TrisCl, pH 7.6, 1mM DTT, 0.01% Final reaction volume of 20 μ L of tween 20. METTL3/14 at 5nM final concentration was preincubated with various compound concentrations for 10 min, followed by the addition of 0.2. Mu.M final concentration of synthetic RNA substrate (5'P-uacacucgaucuggacuaaagcugcuc-3') and 0.5. Mu.M final concentration of S-adenosyl-methionine (SAM). The reaction was incubated at room temperature for an additional 60 minutes, and then TCA and two internal product standards (D) were reduced by the addition of 40 μ L7.5% ₄ -SAH and ¹³ C ₁₀ -SAH) quenching. After termination, the plates were sealed, centrifuged and stored at 4 ℃ until analysis.

Mass spectrometric analysis

Using RapidFire ^TM Mass spectrum (RapidFire) ^TM mass spectrometry, RF/MS) platform measures RNA methyltransferase activity label-free. The stopped and stabilized assay plates were analyzed on an Agilent RF300 integrated autosampler/Solid Phase Extraction (SPE) system connected to an abciex 4000 mass spectrometer for production of the product S-adenosyl homocysteine (SAH) and normalized to the ratio of the signals of the two internal product standards, respectively. Solvent A is water containing 0.1% (v/v) TCA. Solvent B was acetonitrile/0.1% ammonium acetate (8,v/v. More specifically, the plate was centrifuged at 4350rpm for 10 minutes, and the sample was aspirated under vacuum for 600 milliseconds before being loaded onto a C18 solid phase extraction column and washed with solvent A at a flow rate of 1.5 mL/minute for 3 seconds. The retained product and internal standard were eluted with solvent B at a flow rate of 1 mL/min for 3 seconds and finally the column was re-equilibrated with solvent a for 500 milliseconds. The mass transition (mass transition) of the product (SAH) was 384.9/135.9Da. Two internal product standards (IS 1: D) ₄ -SAH and IS2: ¹³ C ₁₀ -SAH) are 389.1/135.8Da and 395.0/134.2Da, respectively. The ratio of SAH/IS1 and SAH/IS2 was used for normalization of the matrix effect. IC50 values were calculated from dilution series of individual compounds. The potency of the compounds was measured at different inhibitor concentrations and normalized to control wells without RNA substrate and without inhibition (DMSO only).

As a result:

TABLE 6

Note: in table 6, IC50=6.1nM indicates the lower limit of the assay.

Kasumi cell assay

Cell culture: CO at 5% at 37 ℃ ₂ KASUMI-1 cells (ACC 20, leibnizz-institute DSMZ German Collection of microorganisms and cell cultures (Leibnizi-institute DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH)) were cultured in RPMI 1640 (31870-025, gibco) supplemented with 20% fetal bovine serum (F1524, gibco), 1mM sodium pyruvate (11360-039, gibco) and 2mM Glutamax (35050-038, gibco) in a humidified incubator.

Cell treatment and cell growth assessment: KASUMI-1 hour was seeded at a final concentration of 250 000 cells/ml (35. Mu.L/well) in ultra-low attachment 384 well plates (MS-9384WZ, SBio) and treated with a compound that inhibits METTL3/14 activity (10 serial semilog dilutions, 30. Mu.M as the highest concentration) for 120 hours. After treatment, kasumi1 cells were incubated with CellTiter-Glo reagent (G7571, promega) for 10 min at room temperature. The measurement of the luminescence signal is carried out on a microplate reader (Ensight, perkinElmer).

As a result: TABLE 7

CTG assay (Caov 3 cell line)

Cell culture: at 37 deg.C in 5% ₂ Caov-3 cells (HTB-75, lot: 70016791, ATCC) were cultured in DMEM (11960-04431053-028, gibco) supplemented with 10% fetal bovine serum (1600-44, gibco), 1mM sodium pyruvate (11360-039, gibco) and 2mM Glutamax (35050-038, gibco) as follows.

Cell treatment and cell growth assessment: caov3 cells were treated with compounds that inhibit METTL3/14 activity (10 semilogarithmic dilutions series, 30. Mu.M as the highest concentration) for 120 hours 18 hours after seeding at 1500 cells/well in white 384-sight plates (6007480, perkinelmer). After treatment, coav-3 cells were incubated with CellTiter-Glo reagent (G7571, promega) for 10 min at room temperature. The measurement of the luminescence signal is carried out on a microplate reader (Ensight, perkinElmer).

Caov3 CTG assay-proliferation assay

TABLE 8

Numbered paragraphs

The following numbered paragraphs are not intended to be claims, but rather are intended to define specific aspects and embodiments of the invention:

1. a compound of formula (I) shown below:

X-Y-Z

(I)

wherein:

x is selected from:

wherein

Q ₁ Selected from NH, N-C _1-4 Alkyl, O or S;

Q _2a selected from N or CR _2a ；

Q _2b Selected from N or CR _2b ；

Q _2c Selected from N or CR _2c ；

Q _2d Selected from N or CR _2d ；

Q ₃ Selected from N or CR _1b ；

Q ₄ Selected from N or CR _1x ；

(i)C _1-4 alkyl or C _1-4 Alkoxy, each of which is optionally substituted by halogen, cyano, hydroxy, C _3-6 Cycloalkyl radical, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, aryl or heteroaryl substitution; or alternatively

(ii) A group of the formula:

-(CR _1c R _1d )p-NR _1e R _1f ；

wherein

p is an integer selected from 0, 1, 2 or 3,

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a salt thereof,

(ii)C _1-6 alkyl, optionally substituted by one or more radicals selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group; and wherein C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally further substituted with halogen, cyano or hydroxy;

(iii)C _3-4 cycloalkyl or 3-to 5-membered heterocyclyl, each of which is optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Substituted in which R _1ca And R _1da Is H or C _1-2 An alkyl group; and

R _1e and R _1f Each independently selected from:

(i) Hydrogen (including deuterium);

(ii)C _1-6 alkyl, optionally substituted by one or more groups selected from cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

(iii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 0, 1, 2, 3, 4, 5 or 6;

R _1g and R _1h Independently selected from:

e) Hydrogen;

f)C _1-6 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy;

g) aryl-C _1-6 Alkyl, heteroaryl C _1-6 Alkyl radical, C _3-6 Cycloalkyl or C _3-6 Cycloalkyl radical C _1-6 Alkyl, each of which is optionally selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; or

h) Or R _1g And R _1h Optionally linked together such that they form, together with the carbon atom to which they are attached, a 3 to 6 membered cycloalkyl or heterocyclic ring, optionally selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy radicalRadical, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group;

and T ₁ Selected from hydrogen, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl group), C _3-8 Cycloalkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (A), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

(iv) Or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro-fused which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0- ₂ R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group;

R _1b selected from hydrogen, cyano, halogen or C _1-3 An alkyl group;

R _1x selected from hydrogen, cyano, halogen or C _1-3 An alkyl group;

-L _2a -L _2b -Q ₂

wherein

Q ₂ Is hydrogen, cyano, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by a group selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, aminosulfonyl, C _1-4 Alkyl, NR _p R _q 、OR _p 、C(O)R _p 、C(O)OR _p 、OC(O)R _p 、C(O)N(R _p )R _q 、N(R _r )C(O)R _p 、S(O) _y R _p (wherein y is 0, 1 or 2), SO ₂ N(R _p )R _q 、N(R _r )SO ₂ R _p Or (CH) ₂ ) _z NR _p R _q (wherein z is 1, 2 or 3) wherein R is _p And R _q Each independently selected from hydrogen or C _1-4 An alkyl group;

y is selected from:

wherein:

n is 0, 1 or 2;

z is selected from one of the following structures:

i)

wherein:

B ₂ is A ₆ Wherein A is ₆ Selected from N or CR ₁₇ Wherein R is ₁₇ 、R _H2 、R _H4 And R _H5 Selected from hydrogen, hydroxy, halogen, cyano, C _1-5 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Halogenoalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon-linked), wherein m is an integer from 1 to 6- (OCH ₂ CH ₂ ) _m -OCH ₃ 、-(OCH ₂ CH ₂ ) _m -NR _q R _r ，NR _q R _r ，-C(O)-NR _q R _r ，-C(O)OR _q ，

Wherein R is _q And R _r Each independently is hydrogen, C _1-5 Alkyl radical, C _3-6 Cycloalkyl, 3-to 6-membered carbon-linked heterocyclyl, or R _q And R _r Linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring;

wherein any C _1-5 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a group selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

B ₃ is N or CR _Z1 Wherein R is _Z1 Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl radicals, in which C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally substituted with one or more of halo, methyl, or methoxy;

B ₄ Selected from C or N;

B ₅ selected from the group consisting of CR _zi1b Or NR _B5N Wherein:

R _B5N Selected from hydrogen or C _1-4 An alkyl group;

B ₇ is N, NR _Z2N Or C-R _Z2 Wherein R is _Z2 Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 An alkoxy group;

B ₈ selected from C or N;

provided that B is ₁ To B ₈ No more than four of which are N.

ii)

Y ₃ is N or CR _z1a Wherein R is _Z1a Selected from hydrogen, hydroxy, C _1-4 Alkyl, cyano, halogen, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl radicals, in which C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally substituted with one or more of halo, methyl, or methoxy;

Y ₄ is C or N;

Y ₅ is CR _Y5 Or NR _Y5N Wherein:

R _Y5N selected from hydrogen or C _1-4 An alkyl group;

Y ₇ is O, S, CR _Z2a Or N, wherein R _Z2a Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 Alkoxy radical；

Y ₈ Is C or N;

Y ₉ Is CR _Z3a Or N; wherein

provided that Y ₁ To Y ₈ No more than four of which are N.

(iii)

X ₂ selected from N or CR ₄ Wherein:

X ₃ is N;

X ₄ is N or C;

X ₅ selected from N, CR ₅ And CRx _5a R _X5b Wherein:

or:

X ₆ is A ₁ And X ₇ Is A ₂ (ii) a Or

X ₆ Is A ₈ And X ₇ Is A ₉ Or A ₁₁ Wherein:

A ₁ selected from the group consisting of CR ₁₂ And N; wherein

R ₁₂ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy and C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and C) _1-4 Alkyl groups);

A ₂ selected from the group consisting of CR ₁₃ And N, wherein:

R ₂₁ is hydrogen or C _1-4 An alkyl group.

R ₂₄ selected from hydrogen or C _1-4 An alkyl group;

R ₂₈ And R ₂₉ Selected from hydrogen, halogen, methoxy and methyl;

R ₃₀ selected from hydrogen or C _1-4 An alkyl group.

X ₈ Selected from the group consisting of CR ₆ N or CR _X6a R _X6b ；

X ₉ is N or C;

provided that X ₂ To X ₉ No more than four of which are N.

(iv)

provided that Z is ₁₀ To Z ₁₆ No more than three of which are N;

(v)

Q ₇ is CR ₇ Or N;

Q ₈ is CR ₈ Or N;

Q ₉ is CR ₉ Or N;

Q ₁₀ is CR ₁₀ Or N;

Q ₁₁ is CR ₁₁ Or N;

Q _11a is NR _11N Or CR _11a R _11b ；

or

R ₉ And R ₁₀ May be linked together such that they form, together with the atoms to which they are attached, a fused 5-or 6-membered saturated or unsaturated ring system, or R ₁₀ And R ₁₁ May be linked together such that they form, together with the atoms to which they are attached, a fused 5-or 6-membered saturated or unsaturated ring system, wherein the fused 5-or 6-membered saturated or unsaturated ring system may optionally be selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ia R _1ja or-S (O) _0- ₂ R _1ia R _1ja Wherein R is substituted with one or more substituents of (A), wherein R is _1ia And R _1ja Is H or C _1-2 An alkyl group;

provided that Q is ₇ To Q ₁₁ No more than three of which are N.

2. A compound of formula (I) according to paragraph 1 or a pharmaceutically acceptable salt thereof,

X-Y-Z

(I)

wherein:

x is selected from:

wherein

Q ₁ Selected from NH, N-C _1-4 Alkyl, O or S;

Q _2a selected from N or CR _2a ；

Q _2b Selected from N or CR _2b ；

Q _2c Selected from N or CR _2c ；

Q _2d Selected from N or CR _2d ；

Q ₃ Selected from N or CR _1b ；

Q ₄ Selected from N or CR _1x ；

(i)C _1-4 alkyl or C _1-4 Alkoxy, each of which is optionally substituted by halogen, cyano, hydroxy, C _3-6 Cycloalkyl, 3-to 6-membered heterocyclyl C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, aryl or heteroaryl substitution; or

(ii) A group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is an integer selected from 0, 1, 2 or 3,

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a salt thereof,

(ii)C _1-6 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group; and wherein C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally further substituted with halogen, cyano, or hydroxy;

(iii)C _3-4 cycloalkyl or 3-to 5-membered heterocyclyl, each of which is optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Substituted in which R _1ca And R _1da Is H or C _1-2 An alkyl group; and is

(iv) Or R _1c And R _1d Are linked together such that they form, together with the carbon atom to which they are attached, a 3 to 6 membered cycloalkyl or heterocyclic ring or a spiro ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 A halogenated alkyl group,Cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group;

R _1e and R _1f Each independently selected from:

(i) Hydrogen (including deuterium);

(ii)C _1-6 alkyl, optionally substituted by one or more radicals selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

(iii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

Wherein:

q is 0, 1, 2, 3, 4, 5 or 6;

R _1g and R _1h Independently selected from:

a) Hydrogen;

b)C _1-6 alkyl, optionally substituted by one or more groups selected from cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (1), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy;

c) aryl-C _1-6 Alkyl, heteroaryl C _1-6 Alkyl radical, C _3-6 Cycloalkyl or C _3-6 Cycloalkyl radical C _1-6 Alkyl, each of which is optionally selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; or alternatively

d) Or R _1g And R _1h Optionally linked together such that they form, together with the carbon atom to which they are attached, a 3 to 6 membered cycloalkyl or heterocyclic ring, optionally selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and is

T ₁ Selected from hydrogen, halogen, C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl group), C _3-8 Cycloalkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, C _3-6 Cycloalkyl, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (1), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

any of which is alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (1), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group;

R _1b selected from hydrogen, cyano, halogen or C _1-3 An alkyl group;

R _1x selected from hydrogen, cyano, halogen or C _1-3 An alkyl group;

-L _2a -L _2b -Q ₂

wherein

y is selected from:

wherein:

n is 0, 1 or 2;

z is selected from:

wherein:

R _Z1 and R _Z1a Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _1-4 Alkoxy radical, C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl radicals, in which C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally substituted with one or more of halo, methyl, or methoxy;

R _Y5N and R _Z2N Selected from hydrogen or C _1-4 An alkyl group;

R _Z12 selected from hydrogen, halogen, cyano、C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

A ₁ selected from the group consisting of CR ₁₂ And N;

A ₂ selected from the group consisting of CR ₁₃ And N;

A ₅ selected from the group consisting of CR ₁₆ And N;

A ₆ selected from the group consisting of CR ₁₇ And N;

A ₇ selected from the group consisting of CR ₁₈ And N;

R ₁₃ selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 The halogenated alkoxy group (for example,hydrogen, halogen, cyano, methoxy, and methyl);

R ₁₇ selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon-linked), wherein m is an integer from 1 to 6- (OCH ₂ CH ₂ ) _m -OCH ₃ 、NR _q R _r Wherein R is _q And R _r Each independently is hydrogen, C _1-5 Alkyl radical, C _3-6 Cycloalkyl, 3-to 6-membered carbon-linked heterocyclyl, or R _q And R _r Linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring; wherein any C _1-5 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a group selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0- ₂ R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

R ₁₉ and R ₂₀ 、R ₂₅ And R ₂₆ Selected from hydrogen, halogen, cyano and C _1-4 An alkyl group;

R ₂₈ and R ₂₉ Selected from hydrogen, halogen, methoxy and methyl;

R ₂₁ 、R ₂₄ and R ₃₀ Is hydrogen or C _1-4 An alkyl group.

3. A compound according to paragraph 1 or 2, wherein X is selected from:

wherein Q ₁ 、R _1a 、R _1b 、R _1x 、R _2a 、R _2b 、R _2c 、R _2d As defined in paragraph 1.

3. A compound according to paragraph 1 or a pharmaceutically acceptable salt thereof, wherein X is selected from:

wherein Q ₁ 、R _1a 、R _1b 、R _2a 、R _2b 、R _2c And R _2d As defined in paragraph 1.

4. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein X is selected from:

wherein Q ₁ 、R _1a 、R _1b 、R _2a 、R _2b And R _2d As defined in paragraph 1.

5. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein X is:

6. A compound according to any one of paragraphs 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Q ₁ Selected from NH or N-C _1-4 An alkyl group.

7. A compound according to paragraph 1 or paragraph 2, or a pharmaceutically acceptable salt thereof, wherein X is selected from:

Wherein R is _1a As defined in paragraph 1 or paragraph 2.

8. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a Selected from:

(ii) A group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a salt thereof,

(ii)C _1-3 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group; and wherein C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano, or hydroxy;

(iii)C _3-4 cycloalkyl or 3-to 5-membered heterocyclyl, each of which is optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Substituted in which R _1ca And R _1da Is H or C _1-2 An alkyl group; and is provided with

R _1e and R _1f Each independently selected from:

(i) Hydrogen (including deuterium);

(ii)C _1-6 alkyl, optionally substituted by one or more radicals selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (1), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

(iii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 0, 1, 2 or 3;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or

b)C _1-3 An alkyl group optionally substituted with one or more substituents selected from the group consisting of: a cyano group; oxo; a hydroxyl group; c _1-3 An alkoxy group; halogen; c _1-4 A haloalkoxy group; -O-C _3-4 Cycloalkyl radicals in which-O-C _3-4 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy; NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is _1ca And R _1da Is H or C _1-2 Alkyl radical NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group;

and T ₁ Selected from hydrogen, halogen, C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl group), C _3-8 Cycloalkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, C _3-6 Cycloalkyl, NR _3t R _4t or-S (O) _0-2 R _3t R _4t One or more ofIs substituted by a substituent, wherein R _3t And R _4t Is H or C _1-2 An alkyl group;

any of alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (1), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

9. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a salt thereof,

(ii)C _1-3 alkyl radical, any of whichOptionally selected from cyano, oxo, hydroxy, C _1-3 Alkoxy, halogen, C _1-43 Haloalkoxy, -O-C _3-4 Cycloalkyl or NH ₂ Substituted with one or more substituents of (a); wherein-O-C _3-6 Cycloalkyl is optionally substituted by halogen, cyano or hydroxy,

(iii) Or R _1c And R _1d Are linked together such that they form, together with the carbon atom to which they are attached, a 3 to 5 membered cycloalkyl or heterocyclic or spirocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group;

R _1e selected from:

(i) Hydrogen (including deuterium);

and R is _1f Selected from:

(i)C _1-6 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy and NH ₂ Substituted with one or more substituents of (a);

(ii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1, 2 or 3;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or

b)C _1-6 Alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 HaloalkoxyRadical, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 Alkyl radical NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy;

c) Or R _1g And R _1h Optionally linked together such that they form, together with the carbon atom to which they are attached, a 3 to 4 membered cycloalkyl or heterocyclic ring, optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (1), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group;

and T ₁ Selected from hydrogen, halogen, C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl group), C _3-8 Cycloalkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, C _3-6 Cycloalkyl, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (A), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

(iii) Or R _1e And R _1f Are connected so that they are connected withThe nitrogen atoms to which they are attached together form a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro-fused which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group;

10. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a salt thereof,

(ii)C _1-3 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-3 Alkoxy, halogen, C _1-3 Haloalkoxy, -O-C _3-4 Cycloalkyl or NH ₂ One or more substituents of (2)Generation; wherein-O-C _3-6 Cycloalkyl is optionally substituted by halogen, cyano or hydroxy,

R _1e Selected from:

(i) Hydrogen (including deuterium);

R _1f is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1, 2 or 3;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or

b)C _1-3 Alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Substituted by one or more substituents of cycloalkyl, wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy;

c) Or R _1g And R _1h Optionally linked together such that they form, together with the carbon atom to which they are attached, a 3 to 4 membered cycloalkyl or heterocyclic ring, optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 (ii) one or more substituents of haloalkoxy;

and T ₁ Selected from halogen, C _1-4 Alkyl radical、C _1-4 Haloalkyl, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl group), C _3-8 Cycloalkyl, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, C _3-6 Cycloalkyl, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (A), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (1), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group;

any of which is alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, haloElement, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (1), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

11. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a salt thereof,

(iii) Or R _1c And R _1d Are linked together such that they form, together with the carbon atom to which they are attached, a 3 to 5 membered cycloalkyl or heterocyclic or spirocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy;

R _1e selected from:

(i) Hydrogen (including deuterium);

R _1f is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1 or 2;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or

b)C _1-3 Alkyl, optionally selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, -O-C ₃ One or more substituents of cycloalkyl, wherein-O-C ₃ Cycloalkyl is optionally substituted with halogen, cyano or hydroxy;

and T ₁ Is selected from C _1-4 Alkyl radical, C _3-8 Cycloalkyl, aryl, heterocyclyl, heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy or C _3-6 Cycloalkyl substituted with one or more substituents;

or R _1e And R _1f Are linked such that together with the nitrogen atom to which they are attached they form a mono-or bicyclic heterocyclic ring, optionally substituted by one or more substituents selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-2 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-2 Alkyl radical, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-2 An alkyl group;

wherein any of themAny alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (A), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

12. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium), or

(ii)C _1-3 Alkyl, optionally selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, -O-C ₃ One or more substituents of the cycloalkyl;

R _1f Is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1 or 2;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or

b)C _1-2 Alkyl, optionally selected from cyano, oxo, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy;

and T ₁ Is selected from C _1-4 Alkyl radical, C _3-8 Cycloalkyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selectedFrom C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy or C _3-6 Cycloalkyl substituted with one or more substituents;

or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 Substituted with one or more substituents of haloalkoxy, and/or by R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy; any of alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (A), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

13. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

p is an integer selected from 1 or 2;

R _1f Is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1 or 2;

and T ₁ Is selected from C _1-4 Alkyl radical, C _3-4 Cycloalkyl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy or C _3-6 One or more substituents of cycloalkyl;

or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 Substituted with one or more substituents of haloalkoxy, and/or by R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro-fused which in turn is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 (ii) one or more substituents of haloalkoxy; wherein any alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (1), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

14. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

p is 1;

R _1f Is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1 or 2;

and T ₁ Is selected from C _3-4 Cycloalkyl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy or C _3-6 Cycloalkyl substituted with one or more substituents;

or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy, and/or by R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 One or more substituents of haloalkoxy; wherein any alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (A), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group.

15. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

R _1f Is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1;

and T ₁ Is selected from C _3-4 Cycloalkyl, heterocyclyl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy or C _3-6 One or more substituents of the cycloalkyl group are substituted,

16. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

p is 1;

R _1c and R _1d Independently selected from hydrogen (including deuterium) or C _1-2 An alkyl group; and is

17. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a The method comprises the following steps:

wherein T is ₁ As defined in any of paragraphs 1 to 16.

18. A compound according to any preceding paragraph, wherein R _1a Selected from:

19. a compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a Selected from:

20. a compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1a Selected from:

21. a compound according to any preceding paragraph or a pharmaceutically acceptable salt thereof, wherein R _1a Selected from:

22. a compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _1b Selected from hydrogen, halogen or C _1-2 An alkyl group.

23. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _2a 、R _2b 、R _2c And R _2d Independently selected from hydrogen, cyano, halogen or a group of the formula:

-L _2a -L _2b -Q ₂

wherein

L _2b is absent or selected from O, S, N (R) _n )、C(O)、C(O)O、OC(O)、C(O)N(R _n )、N(R _n )C(O)、N(R _n )C(O)N(R _o ) Wherein R is _n And R _o Each independently selected from hydrogen or C _1-2 An alkyl group; and is provided with

Q ₂ Is hydrogen, cyano, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by a group selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, aminosulfonyl, C _1-4 Alkyl, NR _p R _q 、OR _p 、C(O)R _p Wherein R is substituted with one or more substituents of (A), wherein R is _p And R _q Each independently selected from hydrogen or C _1-4 An alkyl group.

24. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _2a 、R _2b 、R _2c And R _2d Independently selected from hydrogen, cyano, halogen or a group of the formula:

-L _2a -L _2b -Q ₂

wherein

L _2a Is absent or is optionally substituted by C _1-2 Alkyl substituted C _1-3 An alkylene group;

L _2b is absent or presentSelected from O, S, N (R) _n ) C (O); and is provided with

Q ₂ Is hydrogen, cyano, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano and hydroxy.

25. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _2a 、R _2b 、R _2c And R _2d Independently selected from hydrogen, cyano, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, halogen, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _3-6 Cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano and hydroxy.

26. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _2a 、R _2b 、R _2c And R _2d Independently selected from hydrogen, cyano, halogen or C _1-3 An alkyl group.

27. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _2a 、R _2b 、R _2c And R _2d Is hydrogen.

28. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R _3a1 、R _3b1 、R _3c1 、R _3d1 、R _3e1 、R _3f1 、R _3g1 、R _3h1 、R _3i1 、R _3j1 、R _3k1 、R _3l1 、R _3m1 、R _3n1 、R _3o1 、R _3p1 、R _3q1 、R _3r1 And R _3s1 Independently selected from hydrogen (including deuterium), C _1-6 An alkyl group; wherein C is _1-6 Alkyl is optionally substituted with one or more substituents selected from halogen, amino, cyano, and hydroxy.

29. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R _3a2 、R _3b2 、R _3c2 、R _3d2 、R _3e2 、R _3f2 、R _3g2 、R _3h2 、R _3i2 、R _3j2 、R _3k2 、R _3l2 、R _3m2 、R _3n2 、R _3o2 、R _3p2 、R _3q2 、R _3r2 And R _3s2 Is hydrogen.

30. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein n is 1.

31. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Y is selected from:

wherein n and R _3a1 、R _3a2 、R _3b1 、R _3b2 、R _3e1 、R _3e2 、R _3i1 、R _3i2 、R _3j1 And R _3j2 As defined in any of the preceding paragraphs.

32. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Y is selected from:

33. a compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Y is selected from:

34. a compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Z is selected from:

wherein:

R ₄ selected from hydrogen, halogen, cyano and methyl;

R ₅ selected from hydrogen, halogen, cyano and methyl;

R ₆ selected from hydrogen, halogen, cyano and methyl;

R ₈ 、R ₉ 、R ₁₀ and R ₁₁ Independently selected from hydrogen, NH ₂ Halogen, cyano and C _1-6 An alkyl group; or

R _Z2 and R _Z2a Selected from hydrogen, C _1-4 Alkyl, cyano, halogen, NH ₂ And C _1-4 Alkoxy radical；

R _Z10 independently selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

R _Z12 independently selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

R _Z13 independently selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

R _Z15 independently selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 A haloalkoxy group;

R _Z16 independently selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 HaloalkoxyA base;

A ₁ selected from the group consisting of CR ₁₂ And N;

A ₂ selected from the group consisting of CR ₁₃ And N;

A ₅ selected from the group consisting of CR ₁₆ And N;

A ₆ selected from the group consisting of CR ₁₇ And N;

A ₇ selected from the group consisting of CR ₁₈ And N;

R ₁₆ and R ₁₈ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, C _3-4 Cycloalkyl, 3-to 4-membered heterocyclyl and C _3-4 A cycloalkoxy group;

R ₁₇ selected from hydrogen; a halogen; a cyano group; c _1-4 An alkyl group; c _1-4 A haloalkyl group; c _1-4 An alkoxy group; c _1-4 A haloalkoxy group; c _2-4 An alkenyl group; c _2-4 An alkynyl group; a phenyl group; 5 or 6 membered or heteroaryl; c _3-6 A cycloalkyl group; -O-C _3-6 A cycloalkyl group; a heterocyclic group; -O-heterocyclyl (carbon-linked); - (OCH) ₂ CH ₂ ) _m -OCH ₃ Wherein m is an integer of 1 to 6; NR (nitrogen to noise ratio) _q R _r Wherein R is _q And R _r Each independently of the other is hydrogen, C _1-5 Alkyl radical, C _3-6 Cycloalkyl, 3-to 6-membered carbon-linked heterocyclyl, or R _q And R _r Linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring; wherein any C _1-5 Alkyl radical, C _1-4 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a substituent selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0- ₂ R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

R ₂₂ and R ₂₃ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy (e.g., hydrogen, halogen, cyano, and methyl);

R ₂₈ and R ₂₉ Selected from hydrogen, halogen, methoxy and methyl;

R ₂₁ 、R ₂₄ and R ₃₀ Is hydrogen or C _1-4 An alkyl group.

34. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein:

(i)R ₄ 、R ₅ 、R _X5a 、R _X5b 、R _Y5 、R ₆ 、R ₇ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R _11a 、R _11b 、R _Z2 、R _Z2a 、R _Z3a 、R _Zi1b 、R _Zi2e 、R _Z9 、R _Z10 、R _Z11 、R _Z12 、R _Z12a 、R _Z13 、R _Z14 、R _Z15 and R _Z16 Is independently selected fromHydrogen, methyl, cyano or halogen; and is provided with

R _B5N 、R _Y5N And R _11N Selected from methyl or hydrogen;

(iv)R ₁₇ selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl, wherein m is an integer from 1 to 6- (OCH) ₂ CH ₂ ) _m -OCH ₃ 、NR _q R _r Wherein R is _q And R _r Each independently is hydrogen, C _1-4 Alkyl, or R _q And R _r Linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring; wherein any C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a group selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group.

(v)R ₂₁ 、R ₂₄ And R ₃₀ Independently selected from hydrogen orA methyl group;

35. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein:

(i)R ₄ 、R ₅ 、R _X5a 、R _X5b 、R _Y5 、R _B5N 、R _Y5N 、R ₆ 、R ₇ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R _11a 、R _11b 、R _11N 、R _Z2 、R _Z2a 、R _Z3a 、R _Zi1b 、R _Zi2e 、R _Z9 、R _Z10 、R _Z11 、R _Z12 、R _Z12a 、R _Z13 、R _Z14 、R _Z15 and R _Z16 Is hydrogen;

(iv)R ₁₇ selected from hydrogen; halogen; a cyano group; c _1-2 An alkyl group; c _1-2 A haloalkyl group; c _1-2 An alkoxy group; c _1-2 A haloalkoxy group; c _2-3 An alkenyl group; c _2-3 An alkynyl group; a phenyl group; 5 or 6 membered or heteroaryl; c _3-6 A cycloalkyl group; -O-C _3-6 A cycloalkyl group; a heterocyclic group; - (OCH) ₂ CH ₂ ) _m -OCH ₃ Wherein m is an integer of 1 to 6; NR (nitrogen to noise ratio) _q R _r Wherein R is _q And R _r Each independently is hydrogen, C _1-2 Alkyl, or R _q And R _r Linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring; wherein any C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, alkynyl,Phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a substituent selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

(v)R ₂₁ 、R ₂₄ and R ₃₀ Is hydrogen;

(vi)R ₂₈ and R ₂₉ Is hydrogen.

36. The compound of any one of the preceding paragraphs, wherein:

when X is present ₆ Is A ₁ When, A ₁ Is CR ₁₂ ；

When X is present ₇ Is A ₂ When, A ₂ Is CR ₁₃ ；

B ₁ Is A ₅ Wherein A is ₅ Is CR ₁₆ ；

B ₂ Is A ₆ Wherein A is ₆ Is CR ₁₇ ；

Y ₂ Is A ₇ In which is CR ₁₈ ；

When X is present ₆ Is A ₈ When, A ₈ Is CR ₁₉ R ₂₀ ；

When X is present ₇ Is A ₉ When, A ₉ Is CR ₂₂ R ₂₃ ；

When X is present ₇ Is A ₁₁ When, A ₁₁ Is CR ₂₈ R ₂₉ ；

And wherein R ₁₂ 、R ₁₃ 、R ₁₆ 、R ₁₇ 、R ₁₈ 、R ₁₉ 、R ₂₀ 、R ₂₁ 、R ₂₂ 、R ₂₃ 、R ₂₈ And R ₂₉ As defined in any of the preceding paragraphs.

37. A compound according to any preceding paragraph or a pharmaceutically acceptable salt thereof, whichIn R ₁₇ Selected from hydrogen; a halogen; a cyano group; c _1-2 An alkyl group; c _1-2 A haloalkyl group; c _1-2 An alkoxy group; c _1-2 A haloalkoxy group; c _2-3 An alkenyl group; c _2-3 Alkynyl; a phenyl group; 5 or 6 membered or heteroaryl; c _3-6 A cycloalkyl group; -O-C _3-6 A cycloalkyl group; a heterocyclic group; -O-heterocyclyl (carbon-linked); - (OCH) ₂ CH ₂ ) _m -OCH ₃ Wherein m is an integer of 1 to 6; NR (nitrogen to noise ratio) _q R _r Wherein R is _q And R _r Each independently of the other is hydrogen, C _1-2 Alkyl, or R _q And R _r Linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring;

wherein any C _1- Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a substituent selected from C _1-2 Alkyl, cyano, C _1-2 A halogenated alkyl group hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group.

38. A compound according to any preceding paragraph, or a pharmaceutically acceptable salt thereof, wherein R ₁₇ Selected from hydrogen; halogen; a cyano group; c _1-4 An alkyl group; c _1-4 A haloalkyl group; c _1-4 An alkoxy group; c _1-4 A haloalkoxy group; c _2-4 An alkenyl group; c _2-4 An alkynyl group; c _3-6 A cycloalkyl group; -O-C _3-4 A cycloalkyl group; a heterocyclic group; - (OCH) ₂ CH ₂ ) _m -OCH ₃ Wherein m is 1, 2 or 3; NR (nitrogen to noise ratio) _q R _r Wherein R is _q And R _r Each independently is hydrogen or C _1-2 An alkyl group;

wherein any C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, -O-C _3-4 Cycloalkyl and heterocyclic compoundsIs optionally further selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen and C _1-2 One or more substituents of haloalkoxy.

39. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R _Z1 And R _Z1a Selected from hydrogen, cyano or halogen.

40. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Z is selected from:

A ₁ 、A ₂ 、A ₅ 、A ₆ 、A ₇ 、A ₈ 、A ₉ 、A ₁₁ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R _Y5N 、R _Z1 、R _Z2 、R _Z10 、R _Z12 、R _Z13 、R _Z14 、R _Z15 、R _Z16 、R _Z2a 、R _Z3a 、R _Z1a 、R _Zi1b and R _Zi2e As defined in any of the preceding paragraphs.

41. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Z is selected from:

wherein A is ₁ 、A ₂ 、A ₅ 、A ₆ 、A ₇ 、A ₈ 、A ₉ 、A ₁₁ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R _Y5N 、R _Z1 、R _Z2 、R _Z10 、R _Z12 、R _Z13 、R _Z14 、R _Z15 、R _Z16 、R _Z2a 、R _Z3a 、R _Z1a 、R _Zi1b And R _Zi2e As defined in any of the preceding paragraphs.

42. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Z is selected from:

wherein R is ₈ 、R ₁₀ 、R ₁₇ 、R ₁₈ And R _Z1 As defined in any one of the preceding paragraphs herein.

43. A compound according to any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Z is selected from:

44. a compound according to paragraph 1, or a pharmaceutically acceptable salt thereof, wherein:

x is

Y is selected from:

and is

Z is selected from:

wherein:

(i)R _1a 、R _1b 、R _2a 、R _2b and R _2d As defined in any preceding paragraph;

(ii)R _3a1 、R _3a2 、R _3b1 、R _3b2 、R _3i1 、R _3i2 、R _3j1 、R _3j2 and n is as defined in any preceding paragraph; and is

(iii)A ₁ 、A ₂ 、A ₅ 、A ₆ 、A ₇ 、R ₄ 、R ₅ 、R ₆ 、R _Z1 、R _Z2 、R _Z10 、R _Z12 、R _Z13 、R _Z14 、R _Z15 、R _Z16 、R _Z2a 、R _Z3a 、R _Zi2e 、R _Zi1b And R _Z2 As defined in any of the preceding paragraphs.

45. A compound according to paragraph 44, or a pharmaceutically acceptable salt thereof, wherein:

x is

Y is

Z is

Wherein:

(ii)n、R _3a1 、R _3a2 、R _3j1 、R _3j2 as defined in any preceding paragraph; and is

(iii)A ₁ 、A ₂ 、A ₅ 、A ₆ 、A ₇ 、R ₄ 、R ₅ 、R ₆ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R _Z1 、R _Z2 、R _Z2a 、R _Z3a 、R _Zi2e 、R _Zi1b As defined in any preceding paragraph.

46. A compound according to paragraph 44, or a pharmaceutically acceptable salt thereof, wherein:

x is

Y is

And is provided with

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined in any preceding paragraph;

(ii)n、R _3a1 and R _3a2 As defined in any preceding paragraph; and is

(iii)A ₁ 、A ₂ 、R ₄ 、R ₅ And R ₆ As defined in any of the preceding paragraphs.

47. A compound or pharmaceutically acceptable salt thereof selected from any one of the following:

N- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -1H-indazole-4-carboxamide

N- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-pyrrolo [3,2-b ] pyridin-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- (1H-indol-6-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- (1H-indol-2-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- (indolizin-2-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- (cyclobutylmethyl) -1- [6- [ [3- (1H-indazol-4-yl) -1,2,4-

Diazol-5-yl]Methyl radical]-1H-indol-2-yl]Methylamine

N- [ (2- { [ (1-cyclobutyl cyclopropyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

N- [ (2- { [ ({ 3-Fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-c ]455 yrin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide

5-chloro-3- (1- ((2- (((cyclobutylmethyl) amino) methyl) -1H-indol-6-yl) methyl) -1H-1,2,3-triazol-4-yl) picolinenitrile; and

48. A compound or pharmaceutically acceptable salt thereof selected from any one of the following:

49. A pharmaceutical composition comprising a compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

50. A compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49, for use in therapy.

51. A compound according to any one of paragraphs 1 to 47, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49, for use in the treatment of a proliferative disorder.

52. A compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49, for use in the treatment of cancer.

53. A compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49 for use in the treatment of leukemia.

54. A compound according to any one of paragraphs 1 to 48 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49 for use in the treatment of AML leukemia or chronic myelogenous leukemia.

55. A compound according to any one of paragraphs 1 to 48 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49, for use in inhibiting METTL3 activity.

56. A compound according to any one of paragraphs 1 to 48 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49, for use in the treatment of an autoimmune disease, a neurological disease, an inflammatory disease or an infectious disease.

57. Use of a compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

58. Use of a compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

59. Use of a compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of leukemia.

60. Use of a compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of AML leukemia or chronic myelogenous leukemia.

61. Use of a compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an autoimmune, neurological, inflammatory or infectious disease.

62. Use of a compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting METTL3 activity.

63. A method of treating a proliferative disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49.

64. A method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of paragraphs 1 to 45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 46.

65. A method of treating leukemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49.

66. A method of treating AML leukemia or chronic myelogenous leukemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of paragraphs 1 to 48 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49.

67. A method of treating an autoimmune disease, a neurological disease, an inflammatory disease, or an infectious disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of paragraphs 1 to 48 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49.

68. A method of inhibiting METTL3 activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49.

69. A method of inhibiting metastasis in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound according to any one of paragraphs 1 to 48, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to paragraph 49.

Claims

1. A compound of formula (I) shown below:

X-Y-Z

(I)

wherein:

x is selected from:

wherein

Q ₁ Selected from NH, N-C _1-4 Alkyl, O or S;

Q _2a selected from N or CR _2a ；

Q _2b Selected from N or CR _2b ；

Q _2c Selected from N or CR _2c ；

Q _2d Selected from N or CR _2d ；

Q ₃ Selected from N or CR _1b ；

Q ₄ Selected from N or CR _1x ；

(ii) A group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f ；

wherein

p is an integer selected from 0, 1, 2 or 3,

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a salt thereof,

(ii)C _1-6 alkyl, optionally substituted by one or more radicals selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group; and wherein C _3-6 Cycloalkyl and-O-C _3-6 Cycloalkyl is optionally further substituted with halogen, cyano, or hydroxy;

R _1e and R _1f Each independently selected from:

(i) Hydrogen (including deuterium);

(iii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 0, 1, 2, 3, 4, 5 or 6;

R _1g and R _1h Independently selected from:

a) Hydrogen;

b)C _1-6 alkyl, optionally selected from cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (A), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano, or hydroxy;

c) aryl-C _1-6 Alkyl, heteroaryl C _1-6 Alkyl radical, C _3-6 Cycloalkyl or C _3-6 Cycloalkyl radical C _1-6 Alkyl, each of which is optionally selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0- ₂ R _1ga R _1ha Wherein R is substituted with one or more substituents of (1), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; or

d)R _1g And R _1h Optionally linked together such that they form, together with the carbon atom to which they are attached, a 3 to 6 membered cycloalkyl or heterocyclic ring, which is optionally substitutedIs selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is substituted with one or more substituents of (1), wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and is

T ₁ Selected from hydrogen, halogen, C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl group), C _3-8 Cycloalkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, C _3-6 Cycloalkyl, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (A), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

(iv) Or R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (1), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro-fused which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group; any of which is alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l Wherein R is substituted with one or more substituents of (1), wherein R is _1k And R _1l Is H or C _1-4 An alkyl group;

R _1b selected from hydrogen, cyano, halogen or C _1-3 An alkyl group;

R _1x selected from hydrogen, cyano, halogen or C _1-3 An alkyl group;

-L _2a -L _2b -Q ₂

wherein

Q ₂ Is hydrogen, cyano, C _1-6 Alkyl radical, C _3-6 Cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which is optionally substituted by a substituent selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, aminosulfonyl, C _1-4 Alkyl, NR _p R _q 、OR _p 、C(O)R _p 、C(O)OR _p 、OC(O)R _p 、C(O)N(R _p )R _q 、N(R _r )C(O)R _p 、S(O) _y R _p (wherein y is 0, 1 or 2), SO ₂ N(R _p )R _q 、N(R _r )SO ₂ R _p Or (CH) ₂ ) _z NR _p R _q (wherein z is 1, 2 or 3) wherein R is _p And R _q Each independently selected from hydrogen or C _1-4 An alkyl group; y is selected from:

wherein:

R _3a2 、R _3b2 、R _3c2 、R _3d2 、R _3e2 、R _3f2 、R _3g2 、R _3h2 、R _3i2 、R _3j2 、R _3k2 、R _3l2 、R _3m2 、R _3n2 、R _3o2 、R _3p2- 、R _3q2 、R _3r2 and R _3s2 Is hydrogen or halogen;

n is 0, 1 or 2;

z is selected from:

wherein:

R ₈ 、R ₉ 、R ₁₀ and R ₁₁ Independently selected from hydrogen, NH ₂ Halogen, cyano, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _1-6 Alkyl, -CH ₂ OCH ₃ 、-CH ₂ SO ₂ CH ₃ 、-SO ₂ CH ₃ 、-NHC(O)CH ₃ and-C (O) NR _v1 R _v2 Wherein R is _v1 And R _v2 Independently selected from hydrogen and methyl; or alternatively

R ₉ And R ₁₀ May be linked together such that they form, together with the atoms to which they are attached, a fused 5-or 6-membered saturated or unsaturated ring system, or R ₁₀ And R ₁₁ May be linked together such that they form, together with the atoms to which they are attached, a fused 5-or 6-membered saturated or unsaturated ring system, wherein the fused 5-or 6-membered saturated or unsaturated ring system may optionally be selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ia R _1ja or-S (O) _0-2 R _1ia R _1ja Wherein R is substituted with one or more substituents of (A), wherein R is _1ia And R _1ja Is H or C _1-2 An alkyl group;

R ₇ and R _11N Independently selected from hydrogen、NH ₂ Halogen, cyano and C _1-6 An alkyl group;

R _Y5N and R _Z2N Selected from hydrogen or C _1-4 An alkyl group;

A ₁ selected from the group consisting of CR ₁₂ And N;

A ₂ selected from the group consisting of CR ₁₃ And N;

A ₅ selected from the group consisting of CR ₁₆ And N;

A ₆ selected from the group consisting of CR ₁₇ And N;

A ₇ selected from the group consisting of CR ₁₈ And N;

R ₁₆ and R ₁₈ Selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _1-4 Haloalkyl, C _1-4 HaloalkoxyBase, C _3-4 Cycloalkyl, 3-to 4-membered heterocyclyl and C _3-4- A cycloalkoxy group;

R ₂₈ and R ₂₉ Selected from hydrogen, halogen, methoxy and methyl;

R ₂₁ 、R ₂₄ and R ₃₀ Is hydrogen or C _1-4 An alkyl group.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from:

wherein Q ₁ 、R _1a 、R _1b 、R _1x 、R _2a 、R _2b 、R _2c 、R _2d As defined in claim 1.

3. The compound according to claim 1 or claim 2, wherein X is selected from:

wherein Q ₁ 、R _1a 、R _1b 、R _2a 、R _2b And R _2d As defined in claim 1.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Q is ₁ Selected from NH or N-C _1-4 An alkyl group.

5. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein X is selected from:

wherein R is _1a As defined in claim 1 or claim 2.

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R _1a Selected from:

(ii) A group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium) and a base compound,

(ii)C _1-3 alkyl, optionally selected from cyano, oxo, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (A), wherein R is _1ca And R _1da Is H or C _1-2 An alkyl group; and wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano, or hydroxy;

R _1e and R _1f Each independently selected from:

(i) Hydrogen (including deuterium);

(iii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 0, 1, 2 or 3;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium); or

b)C _1-3 Alkyl optionally substituted with one or more substituents selected from: a cyano group; oxo; a hydroxyl group; c _1-3 An alkoxy group; halogen; c _1-4 A haloalkoxy group; -O-C _3-4 Cycloalkyl radicals of which-O-C _3-4 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy; NR (nitrogen to noise ratio) _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is _1ca And R _1da Is H or C _1-2 Alkyl radical NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; or alternatively

(iv) Or R _1e And R _1f Are linked such that together with the nitrogen atom to which they are attached they form a mono-or bicyclic heterocyclic ring, optionally substituted by one or more substituents selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro-fused, optionally with C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group; wherein any alkyl, alkoxy or C _3-6 Cycloalkyl is further optionally selected from cyano, hydroxy, halogen, NR _1k R _1l or-S (O) _0-2 R _1k R _1l One or more substituents ofIs substituted in which R _1k And R _1l Is H or C _1-4 An alkyl group.

7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

p is an integer selected from 1 or 2;

R _1c and R _1d Independently selected from:

(i) Hydrogen (including deuterium), or

R _1e and R _1f Each independently selected from:

(i) Hydrogen (including deuterium);

(ii)C _1-6 alkyl, optionally selected from cyano, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy and NH ₂ Substituted with one or more substituents of (a);

(iii) A group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 0, 1, 2 or 3;

R _1g and R _1h Independently selected from:

a) Hydrogen (including deuterium);

b)C _1-6 alkyl, optionally selected from cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, -O-C _3-6 Cycloalkyl, NR _1ca R _1da or-S (O) _0-2 R _1ca R _1da Wherein R is substituted with one or more substituents of (1), wherein R is _1ca And R _1da Is H or C _1-2 Alkyl radical NR _1ga R _1ha or-S (O) _0-2 R _1ga R _1ha Wherein R is _1ga And R _1ha Is H or C _1-2 An alkyl group; and wherein-O-C _3-6 Cycloalkyl is optionally substituted with halogen, cyano or hydroxy; or

and T ₁ Selected from hydrogen, halogen, C _1-4 Alkyl radical, C _1-4 Haloalkyl, cyano, hydroxy, NR _1t R _2t or-S (O) _0-2 R _1t R _2t (wherein R is _1t And R _2t Is H or C _1-4 Alkyl group), C _3-8 Cycloalkyl radical, C _2-3 Alkenyl radical, C _2-3 Alkynyl, aryl, heterocyclyl, mono-or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring system, bridged C _3-8 Cycloalkyl, bridged bicyclic C _5-12 Cycloalkyl or a bridged heterocyclic ring system, each of which is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyanoHydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, C _3-6 Cycloalkyl, NR _3t R _4t or-S (O) _0-2 R _3t R _4t Wherein R is substituted with one or more substituents of (A), wherein R is _3t And R _4t Is H or C _1-2 An alkyl group;

(iv) Or R _1e And R _1f Are linked such that together with the nitrogen atom to which they are attached they form a mono-or bicyclic heterocyclic ring, optionally substituted by one or more substituents selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (A), wherein R is _1i And R _1j Is H or C _1-4 Alkyl, and/or from R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-4 Alkoxy, halogen, C _1-4 Haloalkoxy, NR _1i R _1j or-S (O) _0-2 R _1i R _1j Wherein R is substituted with one or more substituents of (1), wherein R is _1i And R _1j Is H or C _1-4 An alkyl group.

8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

R _1f Is a group having the formula:

-(CR _1g R _1h ) _q -T ₁

wherein:

q is 1;

wherein any alkyl or alkoxy group is optionally further substituted with one or more substituents selected from cyano, hydroxy or halogen.

9. A compound according to any one of the preceding claims, wherein R _1a Is a group of the formula:

-(CR _1c R _1d ) _p -NR _1e R _1f

wherein

p is 1;

R _1e And R _1f Are linked such that they form, together with the nitrogen atom to which they are attached, a mono-or bicyclic heterocyclic ring, optionally substituted by C _1-2 Alkyl radical, C _1-2 Haloalkyl, C _3-6 Cycloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 Substituted with one or more substituents of haloalkoxy, and/or by R _1e And R _1f The mono-or bicyclic heterocyclic ring formed optionally with C _3-6 Cycloalkyl or heterocyclic ring spiro fused, which in turn is optionally selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen or C _1-2 Halogenated alkoxyIs substituted with one or more substituents of (a).

10. A compound according to any one of claims 1 to 7, wherein R _1a Selected from:

11. a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R _1b Selected from hydrogen, halogen or C _1-2 An alkyl group.

12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R _2a 、R _2b 、R _2c And R _2d Independently selected from hydrogen, cyano, halogen or C _1-3 An alkyl group.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y is selected from:

14. the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z is selected from:

wherein A is ₁ 、A ₂ 、A ₅ 、A ₆ 、A ₇ 、A ₈ 、A ₉ 、A ₁₁ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R _11N 、R ₁₂ 、R ₁₃ 、R ₁₉ 、R ₂₂ 、R _Z1 、R _Z2 、R _Z2N 、R _z9 、R _Z10 、R _Z11 、R _Z12 、R _Z13 、R _Z14 、R _Z15 、R _Z16 、R _Z2a 、R _Z3a 、R _Z1a 、R _Zi1b And R _Zi2e As defined in any one of the preceding claims.

15. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein:

(i)R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R _11a 、R _11b 、R _Z2 、R _Z2a 、R _Z3a 、R _Zi1b 、R _Zi2e 、R _Z9 、R _Z10 、R _Z11 、R _Z12 、R _Z12a 、R _Z13 、R _Z14 、R _Z15 And R _Z16 Independently selected from hydrogen, methyl, cyano or halogen; and is provided with

R _Y5N 、R _Z2N And R _11N Selected from methyl or hydrogen;

(iv)R ₁₇ selected from hydrogen, halogen, cyano, C _1-4 Alkyl radical, C _1-4 Haloalkyl, C _1-4 Alkoxy radical, C _1-4 Haloalkoxy, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl, - (OCH) wherein m is an integer of 1 to 6 ₂ CH ₂ ) _m -OCH ₃ 、NR _q R _r Wherein R is _q And R _r Each independently of the other is hydrogen, C _1-4 Alkyl, or R _q And R _r Linked together such that they form, together with the nitrogen atom to which they are attached, a 3-to 6-membered heterocyclic ring; wherein any C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, phenyl, 5-or 6-membered or heteroaryl, C _3-6 Cycloalkyl, -O-C _3-6 Cycloalkyl, heterocyclyl or-O-heterocyclyl (carbon-linked) optionally further substituted by a group selected from C _1-2 Alkyl, cyano, C _1-2 Haloalkyl, hydroxy, C _1-2 Alkoxy, halogen, C _1-2 Haloalkoxy, NR _1ea R _1fa or-S (O) _0-2 R _1ea R _1fa Wherein R is substituted with one or more substituents of (A), wherein R is _1ea And R _1fa Is H or C _1-2 An alkyl group;

16. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R ₁₇ Selected from hydrogen; halogen; a cyano group; c _1-4 An alkyl group; c _1-4 A haloalkyl group; c _1-4 An alkoxy group; c _1-4 A haloalkoxy group; c _2-4 An alkenyl group; c _2-4 Alkynyl; c _3-6 A cycloalkyl group; -O-C _3-4 A cycloalkyl group; a heterocyclic group; - (OCH) ₂ CH ₂ ) _m -OCH ₃ Wherein m is 1, 2 or 3; NR (nitrogen to noise ratio) _q R _r Wherein R is _q And R _r Each independently is hydrogen or C _1-2 An alkyl group;

wherein any C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl or ring systems optionally being selected from C _1-2 Alkyl radical, C _1-2 Haloalkyl, cyano, hydroxy, C _1-2 Alkoxy, halogen and C _1-2 One or more substituents of haloalkoxy.

17. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z is selected from:

A ₁ 、A ₂ 、A ₅ 、A ₆ 、A ₇ 、A ₈ 、A ₉ 、A ₁₁ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R _Y5N 、R _Z1 、R _Z2 、R _Z10 、R _Z12 、R _Z13 、R _Z14 、R _Z15 、R _Z16 、R _Z2a 、R _Z3a 、R _Z1a 、R _Zi1b and R _Zi2e As defined in any one of the preceding claims.

18. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

x is

Y is selected from:

and is

Z is selected from:

wherein:

(i)R _1a 、R _1b 、R _2a 、R _2b and R _2d As defined in any one of the preceding claims;

(ii)R _3a1 、R _3a2 、R _3b1 、R _3b2 、R _3i1 、R _3i2 、R _3j1 、R _3j2 and n is as defined in any one of the preceding claims; and is

(iii)A ₁ 、A ₂ 、A ₅ 、A ₆ 、A ₇ 、R ₄ 、R ₅ 、R ₆ 、R ₈ 、R ₉ 、R ₁₀ 、R ₁₁ 、R _Z1 、R _Z2 、R _Z10 、R _Z12 、R _Z13 、R _Z14 、R _Z15 、R _Z16 、R _Z2a 、R _Z3a 、R _Zi2e 、R _Zi1b And R _Z2 As defined in any one of the preceding claims.

19. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

X is

Y is

And is provided with

Z is

(i) Wherein R is _1a 、R _1b 、R _2a 、R _2b And R _2d As defined in any one of the preceding claims;

(ii)n、R _3a1 and R _3a2 As defined in any one of the preceding claims; and is

(iii)A ₁ 、A ₂ 、R ₄ 、R ₅ And R ₆ As defined in any one of the preceding claims.

20. A compound or pharmaceutically acceptable salt thereof selected from any one of the following:

n- ({ 2- [ (4,4-dimethylpiperidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ [ (3,3-difluorocyclobutyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ [ (1-methylcyclopropyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- (2-azabicyclo [2.1.1] hex-2-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

N- [ [2- (3-azabicyclo [3.1.1] heptan-3-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ [2- (hydroxymethyl) pyrrolidin-1-yl ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- (morpholinomethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (1-adamantylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- [ [2- (1-piperidinylmethyl) -1H-indol-6-yl ] methyl ] pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (4-fluoro-1-piperidinyl) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- [ [2- [ [ [ rac- (1s, 2s, 4s) -7-oxabicyclo [2.2.1] hept-5-en-2-yl ] methylamino ] methyl ] -1H-indol-6-yl ] methyl ] pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ [ (1-hydroxycyclopentyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- [ [2- [ [ [ rac- (1s, 2r, 4s) -7-oxabicyclo [2.2.1] hept-5-en-2-yl ] methylamino ] methyl ] -1H-indol-6-yl ] methyl ] pyrido [1,2-a ] pyrimidine-2-carboxamide;

N- [ [2- [ (1-bicyclo [1.1.1] pentylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (cyclobutylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ ({ bicyclo [2.2.1] heptan-2-yl } amino) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (cyclopropylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- (2-azabicyclo [2.2.2] octan-2-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ [ (2,2-difluorocyclopropyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ ({ 3-fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (cyclohexylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ [ (1-hydroxycyclohexyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

N- [ [2- [ (cyclopentylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (cyclopentylmethyl amino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ [ (1-methoxycyclobutyl) methylamino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (isobutylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (cyclohexylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (cyclopropylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- [ [2- [ (prop-2-ynylamino) methyl ] -1H-indol-6-yl ] methyl ] pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (oxetan-2-ylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (2,2-dimethylpropylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (1-bicyclo [1.1.1] pentylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

N- { [2- ({ [ (1s, 2s) -2-hydroxycyclopentyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ [ (1r, 2r) -2-hydroxycyclopentyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ [ (1s, 2r) -2-hydroxycyclopentyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ [ (1r, 2s) -2-hydroxycyclopentyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (cyclopropylmethylamino) methyl ] -5-fluoro-1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (cyclobutylmethylamino) methyl ] -5-fluoro-1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- [ [2- [ (2,2,2-trifluoroethylamino) methyl ] -1H-indol-6-yl ] methyl ] pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ N- (cyclobutylmethyl) acetylamino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- { [2- (piperidin-2-yl) -1H-indol-6-yl ] methyl } -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

N- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -3-fluoro-1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1-methyl-1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (cyclobutylmethylamino) -dideutero-methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] -1H-indazole-4-carboxamide;

n- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-pyrrolo [3,2-b ] pyridin-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- (1H-indol-6-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- (1H-indol-2-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- (indoxazin-2-ylmethyl) -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (6- { [4- (1H-indazol-4-yl) -1H-1,2,3-triazol-1-yl ] methyl } -1H-indol-2-yl) methyl ] cyclopropylamine;

(1r, 2s) -2- [ [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamino ] cyclopentanol;

n- [ [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methyl ] cyclopentylamine;

N- (cyclopropylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine;

1- [ [ [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamino ] methyl ] cyclobutanol;

n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine;

n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-b ] pyridin-2-yl ] methylamine;

n- (cyclobutylmethyl) -1- [6- [ [4- (1H-indazol-4-yl) triazol-1-yl ] methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methylamine;

2- [1- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-indol-6-yl ] methyl ] triazol-4-yl ] pyrido [1,2-a ] pyrimidin-4-one;

n- (cyclobutylmethyl) -1- [6- [ [4- (6-methoxyimidazo [1,5-a ] pyridin-8-yl) triazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine;

1- [6- [ [4- (1H-indazol-4-yl) imidazol-1-yl ] methyl ] -1H-indol-2-yl ] methylamine;

n- (cyclobutylmethyl) -1- [6- [ [3- (1H-indazol-4-yl) -1,2,4-

Diazol-5-yl]Methyl radical]-1H-indol-2-yl]A methylamine;

N- [ [2- (2-azaspiro [3.3] heptan-2-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (benzylamino) methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- (3-azabicyclo [3.1.0] hex-3-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ [ cyclobutylmethyl (methyl) amino ] methyl ] -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ [2- [ (cyclobutylmethylamino) methyl ] -1H-pyrrolo [2,3-b ] pyridin-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-1,3-benzooxadiazol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (but-2-yn-1-yl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (3-cyclopropylprop-2-yn-1-yl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ ({ bicyclo [3.1.0] hex-6-yl } amino) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

N- [ (2- { [ ({ bicyclo [2.1.1] hex-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ ({ 3-methylbicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (3-methylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (3-fluoroazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (azetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ 2-azaspiro [3.4] octan-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (3-hydroxyazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (3,3-dimethylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- [ (2- { [3- (2,2,2-trifluoroethoxy) azetidin-1-yl ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

N- [ (2- { [3- (difluoromethyl) azetidin-1-yl ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (3-methoxyazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [3- (tert-butoxy) azetidin-1-yl ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- [ (2- { [3- (trifluoromethyl) azetidin-1-yl ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (3-ethoxyazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ 2-azaspiro [3.5] nonan-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (2-methylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (3,3-dimethylpyrrolidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ 6-fluoro-2-azaspiro [3.3] heptan-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

N- { [2- ({ 6,6-difluoro-2-azaspiro [3.3] heptan-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (3-cyclobutyl-azetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (3-cyclopropylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (3-tert-butylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (1-tert-butylcyclopropyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ [ (3-methylcyclobutyl) methyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- [ (2- { [ (2,3,3-trimethylbutan-2-yl) amino ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ ({ imidazo [1,2-a ] pyridin-2-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (3,3-diethylazetidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- [ (2- { [ (pent-3-yn-1-yl) amino ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ 6-azaspiro [3.4] octan-6-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ (2,2-dimethylpyrrolidin-1-yl) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ octahydrocyclopenta [ c ] pyrrol-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ 5-azaspiro [2.4] heptan-5-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ ({ 3-methoxybicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- [ (2- { [ ({ spiro [2.2] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- ({ 2- [ ({ spiro [2.3] hex-1-yl } amino) methyl ] -1H-indol-6-yl } methyl) -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ ({ 3-cyanobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

N- { [2- ({ 1-oxa-6-azaspiro [3.4] octan-6-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ 2-azaspiro [4.4] nonan-2-yl } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (1-methylcyclopentyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- (hydroxymethyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (1-cyclobutyl cyclopropyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- { [2- ({ [ (1-methylcyclobutyl) methyl ] amino } methyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4-oxo-N- [ (2- { [ ({ spiro [2.3] hex-5-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- ({ 2- [ ({ [3- (fluoromethyl) bicyclo [1.1.1] pentan-1-yl ] methyl } amino) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (1- { 3-fluorobicyclo [1.1.1] pentan-1-yl } ethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

N- ({ 2- [ (tert-butylamino) methyl ] -1H-indol-6-yl } methyl) -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

4- (1- { [2- ({ 2-azaspiro [3.3] heptan-2-yl } methyl) -1H-indol-6-yl ] methyl } -1H-1,2,3-triazol-4-yl) -1H-indazole;

n- { [2- (2- { 2-azaspiro [3.3] heptan-2-yl } ethyl) -1H-indol-6-yl ] methyl } -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

({ 3-fluorobicyclo [1.1.1] pentan-1-yl } methyl) ({ 6- [ (4- { imidazo [1,5-a ] pyridin-8-yl } -1H-1,2,3-triazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine;

n- [ (2- { [ ({ 3-fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-indol-6-yl) methyl ] -5-oxo-5H- [1,3] thiazolo [3,2-a ] pyrimidine-7-carboxamide;

n- [ (2- { [ ({ bicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-b ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ ({ 3-fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-b ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-pyrrolo [3,2-b ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

N- [ (2- { [ ({ 3-methylbicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-c ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-pyrrolo [3,2-c ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ ({ bicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-c ] pyridin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ ({ 3-fluorobicyclo [1.1.1] pentan-1-yl } methyl) amino ] methyl } -1H-pyrrolo [3,2-c ]501 yrin-6-yl) methyl ] -4-oxo-4H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -4-oxo-4H, 6H,7H,8H, 9H-pyrido [1,2-a ] pyrimidine-2-carboxamide;

(cyclobutylmethyl) ({ 6- [ (4- { 1H-pyrrolo [2,3-b ] pyridin-5-yl } -1H-imidazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine;

(cyclobutylmethyl) ({ 6- [ (4- { imidazo [1,5-a ] pyridin-8-yl } -1H-1,2,3-triazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine;

n- [ (2- { [ (2,2-dimethylpropyl) amino ] methyl } -1H-indol-6-yl) methyl ] -1H-pyrrolo [2,3-b ] pyridine-5-carboxamide;

N- [ (2- { [ (cyclobutylmethyl) amino ] methyl } -1H-indol-6-yl) methyl ] -1H-pyrrolo [2,3-b ] pyridine-5-carboxamide;

(cyclobutylmethyl) ({ 6- [ (4- { 1H-pyrrolo [2,3-b ] pyridin-5-yl } -1H-1,2,3-triazol-1-yl) methyl ] -1H-indol-2-yl } methyl) amine;

n- [ [2- (2-azabicyclo [2.2.1] heptan-2-ylmethyl) -1H-indol-6-yl ] methyl ] -4-oxo-pyrido [1,2-a ] pyrimidine-2-carboxamide;

n- [ (3-fluoro-1-bicyclo [1.1.1] pentyl) methyl ] -1- [6- [ (4-imidazo [1,5-a ] pyridin-8-yltriazol-1-yl) methyl ] -1H-pyrrolo [3,2-c ] pyridin-2-yl ] methylamine;

(cyclobutylmethyl) [ (6- { [1- (1H-indazol-4-yl) -1H-1,2,3-triazol-4-yl ] methyl } -1H-indol-2-yl) methyl ] amine;

[ (3,3-difluorocyclobutyl) methyl ] [ (6- { [1- (1H-indazol-4-yl) -1H-1,2,3-triazol-4-yl ] methyl } -1H-indol-2-yl) methyl ] amine;

(cyclobutylmethyl) [ (6- { [1- (isoquinolin-4-yl) -1H-1,2,3-triazol-4-yl ] methyl } -1H-indol-2-yl) methyl ] amine;

(cyclobutylmethyl) ({ 6- [ (1- { imidazo [1,5-a ] pyridin-8-yl } -1H-1,2,3-triazol-4-yl) methyl ] -1H-indol-2-yl } methyl) amine;

5-chloro-3- (1- ((2- (((cyclobutylmethyl) amino) methyl) -1H-indol-6-yl) methyl) -1H-1,2,3-triazol-4-yl) picolinonitrile; and

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

22. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in therapy.

23. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in the treatment of a proliferative disorder.

24. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in the treatment of cancer.

25. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in the treatment of leukemia.

26. A compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21, for use in the treatment of an autoimmune disease, a neurological disease, an inflammatory disease, an infectious disease or a disease associated with silent X chromosome reactivation.